The DOI matches its Crossref record; 301 of the 302 references it cites were found in a registry or an index; 6 of the 314 sources its claims cite were checked for support.
Pancreatic cancer: Advances and challenges
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant disease.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This review surveys how genomic drivers, the tumor microenvironment, metabolism, transcriptional subtypes, and new single-cell/spatial tools have reshaped understanding of pancreatic ductal adenocarcinoma, while noting that clinical gains remain limited. It argues that translating these biological insights into combination and biomarker-guided therapies is needed to improve the poor survival of this disease.
Key findings
- PDAC is the third leading cause of cancer death in the United States and is projected to pass colorectal cancer before 2040; only about 12% of patients are predicted to survive beyond 5 years. Surgery is possible in only 15–20% at diagnosis, and even after resection nearly 3 in 4 patients recur within two years.
- Early detection strongly affects outcome: patients with Stage IA/IB disease had about 80% five-year survival versus less than 10% for advanced disease, but such low-stage cases make up only 3–5% of diagnoses. In a high-risk surveillance trial, almost three-fourths of detected PDAC were Stage I and the same proportion were alive at five years. Neoadjuvant chemoradiation plus adjuvant chemotherapy improved five-year overall survival to 20.5% versus 6.5% with upfront surgery plus adjuvant therapy.
- Genomic drivers are well defined: KRAS mutations occur in over 90% of samples, with KRASG12C in only 1.6% and KRASG12D in more than 40%; germline Fanconi anemia pathway mutations account for 5–7%, and KRAS wild-type alternative drivers for 8–10%. TP53, SMAD4, and CDKN2A loss are common, and CDKN2A/9p21 interferon-cluster loss is linked to an immune-cold environment.
- The TME and metabolism drive resistance: CAFs, extracellular matrix, suppressive myeloid and adaptive immune populations, and metabolic crosstalk involving alanine, lactate, pyrimidines, and other substrates support tumor growth and therapy escape. Transcriptional subtypes have largely coalesced around classical and basal-like states, with the COMPASS trial showing better first-line 5-FU-based responses in classical tumors; single-cell and spatial methods reveal extensive intratumoral heterogeneity.
Methods
- Narrative review; no original patient cohort, clinical trial, or laboratory experiment is reported. It synthesizes published literature, preclinical models, and clinical trial results.
- Thematically organized around treatment paradigms, precursor lesions, genomic drivers, cell-of-origin, transcriptional subtypes, TME, metabolism, new technologies, and clinical trial design.
- Main analysis is qualitative synthesis and interpretation; no systematic search, meta-analysis, or formal risk-of-bias assessment is described.
Limitations
- The paper states that biomarker research is not covered in depth and that cancer vaccines and antibody-drug conjugates are outside its scope.
- Evident from the text: as a narrative review, it does not use a systematic search strategy or formal evidence grading, so selection and interpretation may be selective.
- Evident: many mechanistic and therapeutic claims rely on mouse or preclinical models, and the authors note preclinical models are imperfect and trial translation has often failed; clinical heterogeneity and subtype plasticity further limit generalization.
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Claims the paper makes
218 Not checked yet · 22 Own interpretation · 9 No basis given · 3 Partly supported · 1 Supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Mutations in the v-Kiras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are found in over 90% of patient samples45.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Supportedcites [45] 2017, Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma, Cancer Cell source
The section “Mutational Heterogeneity of KRAS Alterations in Pancreatic Cancer” (p. 5) reports KRAS mutations in 93% (140/150) of the PDAC samples, which supports “over 90%.” The Discussion (p. 12) repeats the 93% estimate. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the genomic landscape of PDAC is also dominated by loss of function alterations of TP53, SMAD4 (also known as DPC4), and CDKN2A45,48–50.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Supportedcites [45] 2017, Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma, Cancer Cell source
The Introduction (p. 2) identifies TP53, SMAD4, and CDKN2A among the key tumor suppressor genes altered in PDAC, and the recurrent-mutations section (p. 3) reports significant mutations in all three. The Somatic Copy Number Aberrations section (p. 4) also reports recurrent SMAD4 and CDKN2A deletions; the inactivation analysis (p. 12) describes multiple mechanisms of CDKN2A downregulation. Together, these passages support the claim’s characterization of prominent loss-of-function alterations. (LLM, conf=0.87)
- Partly supportedcites [48] Jones, 2008, Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science sourceExperimental — accuracy not yet measured
The Deletions section identifies TP53, SMAD4, and CDKN2A as classic tumor suppressor genes affected by homozygous deletions, which abrogate gene function. But the paper does not say that loss-of-function alterations in these three genes dominate the PDAC genomic landscape; its Implications for Pancreatic Tumorigenesis section instead emphasizes 12 altered pathways whose affected genes vary among tumors. (LLM, conf=0.84)
- Supportedcites [49] Waddell, 2015, Whole genomes redefine the mutational landscape of pancreatic cancer, Nature source
The ‘Genes affected by mutation and structural variation’ section identifies TP53, SMAD4 and CDKN2A as commonly mutated PDAC genes and reports inactivation events in 74%, 31% and 35% of cases, respectively. That supports the claim’s characterization of these loss-of-function alterations as prominent features of the PDAC genomic landscape. (LLM, conf=0.91)
- Not checked yetcites [50] Bailey, 2016, Genomic analyses identify molecular subtypes of pancreatic cancer, Nature source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“despite showing potent growth inhibitory effects in short-term PDAC cell proliferation assays, GLS inhibition was found to be ineffective in pancreatic tumor models through remodeling of compensatory metabolic pathways199”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Partly supportedcites [199] Bott, 2019, Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism, Cell Rep. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) states that GLS ablation does not have an overt effect on PDAC development in vivo, supporting the tumor-model portion of the claim. It does not report potent growth inhibition from GLS inhibition in short-term PDAC proliferation assays or attribute the in-vivo result to remodeling of compensatory metabolic pathways; the paper’s own experiments concern GLUL. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
In the paper
“patients whose PDAC exhibits a major or complete pathological response to neoadjuvant therapy demonstrate significantly improved overall survival17”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [17] Cloyd, 2017, Association of clinical factors with a major pathologic response following preoperative therapy for pancreatic ductal adenocarcinoma, JAMA Surg. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“nearly 3 in 4 of patients will develop recurrence within two years”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [11] Groot, 2018, Patterns, timing, and predictors of recurrence following pancreatectomy for pancreatic ductal adenocarcinoma, Ann. Surg. source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“a multitude of circulating tumor-derived analytes (proteins, autoantibodies, metabolites, DNA, non-coding RNAs and extracellular vesicles, among others) have been assessed in the context of PDAC early detection39–41.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [39] Chari, 2015, Early detection of sporadic pancreatic cancer: summative review, Pancreas source
- Not checked yetcites [40] Singhi, 2021, Early detection of pancreatic cancer using DNA-based molecular approaches, Nat. Rev. Gastroenterol. Hepatol. source
- Not checked yetcites [41] Pereira, 2020, Early detection of pancreatic cancer, Lancet Gastroenterol. Hepatol. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Approximately 85–90% of PDAC cases are ascribed to originate on the backdrop of PanIN lesions, the remaining 10–15% in cystic precursors20.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [20] Singhi, 2019, Early detection of pancreatic cancer: opportunities and challenges, Gastroenterology source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“outside of the minority (10–15%) of cases ascribed to germline mutations or known risk factors, such as mucinous cystic lesions and chronic pancreatitis, there is no single attributable risk factor for most patients4.”
§ Pancreatic Cancer: Advances and Challenges > Introduction:
What the sources say
- Not checked yetcites [4] Petersen, 2016, Familial pancreatic cancer, Semin. Oncol. source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“More recent IPMN models have been generated that genocopy recurrent driver alterations observed in cognate human lesions (i.e. Kras, Gnas, Rnf43) (Fig 1)34–36, and these models demonstrate the comparable stepwise progression observed in patient derived IPMNs.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [34] Ideno, 2018, GNAS(R201C) induces pancreatic cystic neoplasms in mice that express activated KRAS by inhibiting YAP1 signaling, Gastroenterology source
- Not checked yetcites [35] Patra, 2018, Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism, Nat. Cell Biol. source
- Not checked yetcites [36] Hosein, 2022, Loss of Rnf43 accelerates kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma, Gastroenterology source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent phylogenetic analyses of precursor lesions from the pancreata of patients with established cancer have confirmed the stepwise progression model and accumulation of genetic alterations in the transition from PanINs to PDAC postulated using more rudimentary techniques26.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [26] Makohon-Moore, 2018, Precancerous neoplastic cells can move through the pancreatic ductal system, Nature source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting patients undergoing resection also harbor micro-metastatic disease11.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [11] Groot, 2018, Patterns, timing, and predictors of recurrence following pancreatectomy for pancreatic ductal adenocarcinoma, Ann. Surg. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“conditional expression of oncogenic mutant Kras in the pancreas, using Cre-recombinase driven by pancreatic transcription factor promoters activated during embryonic development, leads to development of murine PanIN lesions histologically reminiscent of human disease28.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [28] Hingorani, 2003, Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“pre-clinical studies have demonstrated that disseminated PDAC cells can be observed in circulation before localized invasion is readily visualized in primary tumors12.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [12] Rhim, 2012, EMT and dissemination precede pancreatic tumor formation, Cell source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“combined expression of oncogenic Kras coupled with the deletion or loss of function of Trp53, Cdkn2a, or Smad4 in the pancreas of mice readily leads to invasive PDAC29–32.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [29] Bardeesy, 2006, Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer, Genes Dev. source
- Not checked yetcites [30] Hingorani, 2005, Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice, Cancer Cell source
- Not checked yetcites [31] Aguirre, 2003, Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma, Genes Dev. source
- Not checked yetcites [32] Qiu, 2011, Disruption of p16 and activation of Kras in pancreas increase ductal adenocarcinoma formation and metastasis in vivo, Oncotarget source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Early molecular profiling coupled with histology allowed for the development of a putative pathological progression model; analogous to the adenoma-carcinoma model in the colon23”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [23] Maitra, 2003, Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray, Mod. Pathol. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“modeling studies performed on the mutational data have estimated that the timeline of multistep progression to invasive neoplasia in the pancreas likely spans multiple years and provides a theoretically wide window of opportunity for early detection27.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [27] Yachida, 2010, Distant metastasis occurs late during the genetic evolution of pancreatic cancer, Nature source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“neoadjuvant chemoradiation in conjunction with adjuvant chemotherapy shows significantly improved five-year overall survival rates compared to patients who received upfront surgery with adjuvant therapy (20.5% versus 6.5%).”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [18] Versteijne, 2022, Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the Dutch randomized PREOPANC trial, J. Clin. Oncol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The factors driving the lethality of PDAC are numerous, centered on an inability to detect the disease until late in progression, often after distant metastasis3.”
§ Pancreatic Cancer: Advances and Challenges > Introduction:
What the sources say
- Not checked yetcites [3] Kleeff, 2016, Pancreatic cancer, Nat. Rev. Dis. Primers source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“only 15–20% of patients are eligible for surgery at diagnosis3.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [3] Kleeff, 2016, Pancreatic cancer, Nat. Rev. Dis. Primers source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“CA19–9 elevations can be observed in plasma samples obtained in the pre-diagnostic setting, suggesting a potential window of opportunity for early detection38.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [38] Fahrmann, 2021, Lead-time trajectory of CA19-9 as an anchor marker for pancreatic cancer early detection, Gastroenterology source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Rests on an assumption: CA19-9 is the most widely used diagnostic biomarker for PDAC but has suboptimal sensitivity in early-stage disease.
In the paper
“the combined haploinsufficiency of Smad4, coupled with oncogenic KRAS expression, leads to the development of cystic neoplasms, linking Kras mutations to other putative PDAC precursor lesions33.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [33] Izeradjene, 2007, Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“murine acinar cells can de-differentiate to a progenitor-like state with a ductal appearance. This has been termed acinar-to-ductal-metaplasia (ADM)110,111”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [110] Means, 2005, Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates, Development source
- Not checked yetcites [111] Miyamoto, 2003, Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Approximately 5–7% of patients with PDAC harbor a germline mutation in one of the Fanconi anemia family of genes (BRCA1, BRCA2, and PALB2) encoding for proteins engaged in homologous recombination repair85.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [85] Zhen, 2015, BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study, Genet. Med. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“withdrawal of mutant Ras signaling in preclinical models that include loss of tumor suppressor function leads to tumors that can re-occur in a Ras-independent fashion67.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [67] Kapoor, 2014, Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The temporal appearance of these alterations during multistep progression suggests that TP53 and SMAD4 typically occur late, usually in the setting of high-grade lesions or cancer in both PanINs and IPMNs23,51.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [23] Maitra, 2003, Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray, Mod. Pathol. source
- Not checked yetcites [51] Sohn, 2001, Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity, Ann. Surg. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“More recent studies have demonstrated that, in addition to patients with germline mutations, those harboring de novo somatic mutations of BRCA1/2 and PALB2 also show benefit from PARP inhibitors, provided there is bi-allelic loss and established homologous repair deficiency in the tumors89.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [89] Momtaz, 2021, Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes, Cancer source
boostedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“bi-allelic mutations of ATM have not been shown to result in susceptibility to PARP inhibitor monotherapy like BRCA1/292,93.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [92] Park, 2022, Clinico-genomic characterization of ATM and HRD in pancreas cancer: application for practice, Clin. Cancer Res. source
- Not checked yetcites [93] Javle, 2021, Olaparib monotherapy for previously treated pancreatic cancer with DNA damage repair genetic alterations other than germline BRCA variants: findings from 2 Phase 2 nonrandomized clinical trials, JAMA Oncol. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“longer follow up data did not demonstrate a similar improvement in overall survival (OS) compared to patients who received placebo alone following platinum-based therapy88.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [88] Kindler, 2022, Overall survival results from the POLO trial: A Phase III study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer, J. Clin. Oncol. source
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“in such an inducible system, PanINs can be observed to re-differentiate back to acinar cells in the absence of tumor suppressor loss66.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [66] Collins, 2014, MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice, Gastroenterology source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“RNAi-mediated gene silencing of oncogenic KRAS revealed a significant portion of PDAC cell lines demonstrate no reliance on KRAS expression for viability62.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [62] Singh, 2009, A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival, Cancer Cell source
boosteddirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The alternative drivers (e.g., ALK, TRK, RET, NRG1, BRAF, EGFR) activate the MAP kinase signaling pathway, reiterating the primacy of this downstream Ras effector to PDAC pathogenesis.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“is associated with higher rates of metastatic dissemination during neoadjuvant therapy and terminal disease55,56.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [55] Iacobuzio-Donahue, 2009, DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer, J. Clin. Oncol. source
- Not checked yetcites [56] Ecker, 2022, Alterations in Somatic Driver Genes Are Associated with Response to Neoadjuvant FOLFIRINOX in Patients with Localized Pancreatic Ductal Adenocarcinoma, J. Am. Coll. Surg. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“PDAC mouse models have suggested TP53 mutations promote a patterned loss of genomic integrity as opposed to a chaotic process60.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [60] Baslan, 2022, Ordered and deterministic cancer genome evolution after p53 loss, Nature source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“SMAD4 loss has a profound deleterious effect on prognosis54”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [54] Blackford, 2009, SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer, Clin. Cancer Res. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the ability of PDAC to survive Ras inhibition highlights a likely challenge of newly developed small molecule inhibitors of mutant KRAS.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“deletion of SWI/SNF factors Arid1a or Brg1 results in the acceleration of pancreatic tumorigenesis on the backdrop of cystic neoplasms resembling human IPMNs98–100.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [98] Livshits, 2018, Arid1a restrains Kras-dependent changes in acinar cell identity, eLife source
- Not checked yetcites [99] Wang, 2019, SWI/SNF component ARID1A restrains pancreatic neoplasia formation, Gut source
- Not checked yetcites [100] von Figura, 2014, The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma, Nat. Cell Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“chromatin regulatory factors may have a more context-specific and biphasic function in PDAC, with studies in autochthonous models suggesting both tumor suppressor and oncogenic functions during distinct stages of tumorigenesis101,102.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [101] Roy, 2015, Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation, Genes Dev. source
- Not checked yetcites [102] Ferri-Borgogno, 2020, Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis, Cancers (Basel) source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“correlative studies conducted in other KRASG12C-mutant tumor types treated with these inhibitors have demonstrated the emergence of pleiotropic resistance through both cell autonomous and non-cell autonomous mechanisms76–78.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [76] Tsai, 2022, Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition, J. Clin. Invest. source
- Not checked yetcites [77] Tanaka, 2021, Clinical acquired resistance to KRAS(G12C) inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation, Cancer Discov. source
- Not checked yetcites [78] Awad, 2021, Acquired resistance to KRAS(G12C) inhibition in cancer, N. Engl. J. Med. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“given the observed resistance to KRASG12C inhibitors and observations from KRAS extinction models, it is probable these drugs will face similar challenges as they enter the clinic.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“there are also so-called “alternative drivers” found in the 8–10% of cases that are KRAS wild type104,105.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [104] Singhi, 2019, Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers, Gastroenterology source
- Not checked yetcites [105] Aguirre, 2018, Real-time genomic characterization of advanced pancreatic cancer to enable Precision medicine, Cancer Discov. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Withdrawal of oncogenic Kras resulted in regression of invasive neoplasia, including regression of metastatic disease63–65.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [63] Collins, 2012, Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice, J. Clin. Invest. source
- Not checked yetcites [64] Ying, 2012, Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source
- Not checked yetcites [65] Collins, 2012, Metastatic pancreatic cancer is dependent on oncogenic Kras in mice, PLoS One source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“data from pre-clinical PDAC models has shown promising responses to a small molecule inhibitor targeting KRASG12D mutations common in PDAC79.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [79] Kemp, 2023, Efficacy of a small molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“lineage tracing analysis of perivascular fibroblasts, expressing the transcription factor Gli1, showed this population expands to form nearly half of pre-CAFs in PanINs and CAFs in cancer”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [144] Huang, 2022, Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“recent lineage tracing studies targeting Fabp4+ stellate cells revealed that they give rise to a minority of CAFs142,143”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [142] Helms, 2022, Mesenchymal lineage heterogeneity underlies nonredundant functions of pancreatic cancer-associated fibroblasts, Cancer Discov. source
- Not checked yetcites [143] Garcia, 2020, Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma, Cell. Mol. Gastroenterol. Hepatol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Bailey and colleagues identified four subtypes of PDAC, which they termed “squamous”, “pancreatic progenitor”, “immunogenic”, and “aberrantly differentiated endocrine exocrine” (ADEX) type tumors50.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [50] Bailey, 2016, Genomic analyses identify molecular subtypes of pancreatic cancer, Nature source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Puleo et al. identified five subtypes, termed “pure basal like”, “stroma activated”, “desmoplastic”, “pure classical”, and “immune classical”133.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [133] Puleo, 2018, Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features, Gastroenterology source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“mesothelial cells, expressing Wilms Tumor 1 (Wt1) also contribute to a sub-population of CAFs145”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [145] Han, 2023, The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis, Nat. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“multiple types have potential to co-exist within induvial tumors134”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [134] Chan-Seng-Yue, 2020, Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution, Nat. Genet. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“tracing the embryonic origin of tissue resident fibroblasts through the splanchnic mesenchyme expressing Isl Lim homeodomain 1 (Isl1) labeled most tissue resident fibroblasts and pancreatic CAFs146”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [146] Öhlund, 2017, Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer, J. Exp. Med. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While not abundant, stellate cell derived CAFs have a tumor promoting role supported by unique gene expression and metabolic profiles.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“lineage tracing studies in mice confirmed that acinar cells can repopulate damaged tissue112.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [112] Desai, 2007, Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration, J. Clin. Invest. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The normal pancreas contains heterogeneous fibroblasts populations (Fig. 2) including pancreatic stellate cells —similar to liver stellate cells and containing vitamin A-rich lipid droplets141— perivascular fibroblasts, and other parenchymal fibroblasts.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [141] Apte, 2004, Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells, Pancreas source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“stabilized expression of PTF1A and MIST1 inhibit PanIN formation in the context of mutant KRAS expression122,123.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [122] Krah, 2015, The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma, eLife source
- Not checked yetcites [123] Shi, 2013, Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia, Oncogene source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“correlating their subtypes with single-cell RNA sequencing data, they demonstrated that different subtypes can co-exist within individual tumors.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [134] Chan-Seng-Yue, 2020, Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution, Nat. Genet. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“the transcriptional landscape of PDAC cells can also be influenced by microenvironmental factors137”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [137] Raghavan, 2021, Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer, Cell source
plainconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The cell state of the classical and basal-like subtypes is potentially plastic”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“parenchymal fibroblasts, expressing Hoxb6 do not expand during carcinogenesis144”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [144] Huang, 2022, Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer, Cancer Cell source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The first direct comparison using adult acinar vs. ductal expression of oncogenic KRAS demonstrated that KRAS promotes acinar cells to generate neoplastic lesions at a frequency over a hundred-fold higher than ductal cells118.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [118] Kopp, 2012, Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma, Cancer Cell source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This was not observed in the context of damage through cerulein-induced pancreatitis118, which drives inflammation through damage of acinar cells.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [118] Kopp, 2012, Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma, Cancer Cell source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the accumulation of evidence in murine models has shown that, in the right context, either acinar or ductal cells can serve as a progenitor population for PDAC (Fig. 1).”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
boostedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“the oncogenic KRAS signaling in the PDAC cells initiates and coordinates the development of this growth supportive niche139”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [139] Velez-Delgado, 2022, Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming, Cell. Mol. Gastroenterol. Hepatol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“They identified three subtypes, termed “classical”, “quasimesenchymal”, and “exocrine-like”130.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [130] Collisson, 2011, Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy, Nat. Med. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Patients with classical subtype of PDAC had superior responses to first line 5-flurouracil-basd regimens than those with “basal-like” cancers138”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [138] Aung, 2018, Genomics-driven Precision medicine for advanced pancreatic cancer: early results from the COMPASS trial, Clin. Cancer Res. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“the deletion of Trp53 leads to the rapid development of invasive carcinoma125–127.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [125] Lee, 2019, Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma, Gut source
- Not checked yetcites [126] Bailey, 2016, p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells, Oncogene source
- Not checked yetcites [127] Flowers, 2021, Cell of origin influences pancreatic cancer subtype, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“a combination of dual labeling approaches and bone marrow transplants showed the contribution of bone marrow progenitors and cancer epithelial cells to the CAF population is minimal146”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [146] Öhlund, 2017, Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer, J. Exp. Med. source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“heterozygous or homozygous deletion of factors associated with terminal acinar differentiation such as Ptf1a, Mist1, and Nr5a2 accelerate KRAS-driven tumorigenesis119–122.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [119] von Figura, 2014, Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation, Gut source
- Not checked yetcites [120] Flandez, 2014, Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRas(G12V)-driven pancreatic tumourigenesis, Gut source
- Not checked yetcites [121] Shi, 2009, Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia, Gastroenterology source
- Not checked yetcites [122] Krah, 2015, The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma, eLife source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the induction of pancreatic damage by pancreatic ductal ligation is sufficient to promote KRAS-mediated ductal-lineage tumorigenesis128.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [128] Shi, 2019, Differential cell susceptibilities to kras(G12D) in the setting of obstructive chronic pancreatitis, Cell. Mol. Gastroenterol. Hepatol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Combining oncogenic KRAS expression in the adult-ductal lineage with Pten loss leads to the formation of IPMNs124”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [124] Kopp, 2018, Loss of Pten and activation of kras synergistically induce formation of intraductal papillary mucinous neoplasia from pancreatic ductal cells in mice, Gastroenterology source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, among resident pancreatic fibroblasts, different populations have vastly different abilities to expand during carcinogenesis.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“CAF populations and their organization of tumor architecture can vary across different regions of tumors creating “sub-tumor microenvironments” within patients156”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [156] Jacobetz, 2013, Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer, Gut source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Tumor-associated macrophages (TAMs) arising from both tissue resident macrophages or circulating monocytes appear to play important but potentially different roles in shaping the TME, and suppression of the adaptive immune response178”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [178] Zhu, 2014, CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models, Cancer Res. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“mechanistic investigation into myCAF and iCAF biology in vitro suggested potential plasticity between the two populations148, dependent on extracellular signaling molecules present.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [148] Elyada, 2019, Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts, Cancer Discov. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“randomized clinical trials combining a pegylated hyaluronic acid degrading enzyme, PEG-hyaluronidase, with standard-of-care chemotherapy for advanced PDAC did not show an increase in overall survival regardless of chemotherapy backbone or selection of patients with high levels of hyaluronic acid by immunostaining172,173”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [172] Van Cutsem, 2020, Randomized Phase III trial of Pegvorhyaluronidase Alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma, J. Clin. Oncol. source
- Not checked yetcites [173] Jiang, 2016, Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy, Nat. Med. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Collagen is the most abundant matrix molecule found in PDAC163”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [163] Imamura, 1995, Quantitative analysis of collagen and collagen subtypes I, III, and V in human pancreatic cancer, tumor-associated chronic pancreatitis, and alcoholic chronic pancreatitis, Pancreas source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Other T cell populations within the TME have all been noted to play protumorigenic roles, including Th17, Th22, CD4, and γδ T cells188–191”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [188] McAllister, 2014, Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia, Cancer Cell source
- Not checked yetcites [189] Perusina Lanfranca, 2020, Interleukin 22 signaling regulates acinar cell plasticity to promote pancreatic tumor development in mice, Gastroenterology source
- Not checked yetcites [190] Zhang, 2014, CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice, Cancer Immunol. Res. source
- Not checked yetcites [191] Zhang, 2020, Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“clinical trials showed a worsened survival with combined hedgehog inhibition and chemotherapy.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
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In the paper
“fibroblast status throughout tumorigenesis and progression can be influenced by genetic mutations present in the PDAC cells154,155”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [154] Vennin, 2019, CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan, Nat. Commun. source
- Not checked yetcites [155] Grünwald, 2021, Spatially confined sub-tumor microenvironments in pancreatic cancer, Cell source
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“One population expresses several components of the antigen presentation machinery typically found on myeloid populations.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [149] Dominguez, 2020, Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy, Cancer Discov. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Initial preclinical data in mouse models suggested that use of hyaluronidase combined with chemotherapy showed great promise140,157”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source
- Not checked yetcites [157] Olive, 2009, Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer, Science source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Collagen also acts as a signaling molecule, activating discoidin domain receptor signaling that shape multiple roles in PDAC pathology168–171”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [168] Ruggeri, 2020, Discoidin domain Receptor 1 (DDR1) is necessary for tissue homeostasis in pancreatic injury and pathogenesis of pancreatic ductal adenocarcinoma, Am. J. Pathol. source
- Not checked yetcites [169] Su, 2022, Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome, Nature source
- Not checked yetcites [170] Aguilera, 2014, Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma, Cancer Res. source
- Not checked yetcites [171] Ramanathan, 2019, Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313, J. Clin. Oncol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“combined treatment of FAK inhibition with immune checkpoint blockade demonstrated tumor regression in an aggressive mouse model of PDAC”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“single-cell mass cytometric analysis has identified that the cell surface marker CD105 can be used to identify two functionally distinct and non-interconvertible populations of CAFs, namely, tumor permissive CD105+ CAFs, and tumor suppressive CD105− CAFs152”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [152] Krishnamurty, 2022, LRRC15(+) myofibroblasts dictate the stromal setpoint to suppress tumour immunity, Nature source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“depletion of stromal fibroblasts through hedgehog inhibition, epithelial sonic hedgehog deletion, stromal ablation, or inhibition of lysyl oxidase like-2 increases tumor access to the blood supply and facilitates metastasis, having deleterious consequences on natural history of the disease159–162”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [159] Özdemir, 2014, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Cancer Cell source
- Not checked yetcites [160] Lee, 2014, Stromal response to Hedgehog signaling restrains pancreatic cancer progression, Proc. Natl. Acad. Sci. USA source
- Not checked yetcites [161] Jiang, 2020, Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix, J. Clin. Invest. source
- Not checked yetcites [162] Perez, 2021, The PDAC extracellular matrix: a review of the ECM protein composition, tumor cell interaction, and therapeutic strategies, Front. Oncol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“combining inhibition of glycolysis with blockade of KRAS effector signaling pathways has shown efficacy in culture and xenograft models197”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [197] Son, 2013, Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“PDAC cells utilize macropinocytosis to obtain amino acids through the uptake and degradation of albumin and collagen230–232”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [230] Commisso, 2013, Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells, Nature source
- Not checked yetcites [231] Davidson, 2016, Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer, Cell Metab. source
- Not checked yetcites [232] Jayashankar, 2020, Macropinocytosis confers resistance to therapies targeting cancer anabolism, Nat. Commun. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“even though CD4 T cell ablation enabled CD8 mediated regression of PDAC tumors in mice”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [192] Kamphorst, 2015, Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein, Cancer Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“this approach can be potentially overcome through compensatory upregulation of oxidative phosphorylation196”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [196] Yan, 2021, Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition, Cancer Res. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“autophagy plays a critical role in maintaining iron homeostasis in PDAC cells214”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [214] Pantopoulos, 2012, Mechanisms of mammalian iron homeostasis, Biochemistry source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mitophagy, the selective engulfment and degradation of mitochondria through autophagy, has also been shown to be important in PDAC tumorigenesis in mice and organoid models211”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [211] Boone, 2015, Safety and biologic response of pre-operative autophagy inhibition in combination with gemcitabine in patients with pancreatic adenocarcinoma, Ann. Surg. Oncol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“analysis of the nutrients available within murine tumor interstitial fluid demonstrates a starkly different profile within pancreatic tumors vs. serum levels194”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [194] Guillaumond, 2013, Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma, Proc. Natl. Acad. Sci. USA source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The autophagy-MHC-I relationship provides mechanistic insight to functional genomics studies in mice, which have also linked autophagy and immune evasion in PDAC228.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [228] Bar-Sagi, 1986, Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Autophagy has also been shown to play important roles in resistance to targeted therapies.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“genetic inhibition of critical autophagy proteins in mice leads to regression of autochthonous PDAC tumors210”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [210] Humpton, 2019, Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Macropinocytosis has also been shown to utilize necrotic cell debris as a fuel source, which can provide sugars, fatty acids, nucleotides, and amino acids to fuel cancer cell metabolism233,234.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [233] Kim, 2018, PTEN deficiency and AMPK activation promote nutrient scavenging and anabolism in prostate cancer cells, Cancer Discov. source
- Not checked yetcites [234] Lee, 2019, EGFR-Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis, Dev. Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Autophagy is critical for cancer cell growth and tumorigenesis in mouse models of PDAC207–209”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [207] Rosenfeldt, 2013, p53 status determines the role of autophagy in pancreatic tumour development, Nature source
- Not checked yetcites [208] Yang, 2014, Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations, Cancer Discov. source
- Not checked yetcites [209] Yang, 2018, Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“clinical trials have shown that hydroxychloroquine, which inhibits autophagic flux by preventing lysosomal acidification, enhances PDAC patient response to chemotherapy212,213”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [212] Zeh, 2020, A randomized Phase II preoperative study of autophagy inhibition with high-dose hydroxychloroquine and gemcitabine/nab-paclitaxel in pancreatic cancer patients, Clin. Cancer Res. source
- Not checked yetcites [213] Mancias, 2014, Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy, Nature source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“macropinocytosis is a non-substrate specific fluid phase uptake process engaged by oncogenic KRAS signaling229”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [229] Olivares, 2017, Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions, Nat. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Genetic or pharmacological inhibition of autophagy in mice bearing PDAC tumors promotes enhanced cell-surface MHC-I expression and antigen presentation, leading to an increased response to immune checkpoint blockade therapy.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Direct measurement of the metabolites in human PDAC tumors revealed classes of metabolites are in low supply for cells within the tumors, and others are increased in abundance193”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [193] Sullivan, 2019, Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability, eLife source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“depletion of FoxP3+ T regulatory cells (Tregs) accelerated tumorigenesis due to compensatory myeloid infiltration192”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [192] Kamphorst, 2015, Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein, Cancer Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Inhibition of the mutant KRAS-MEK-MAPK signaling cascade using ERK inhibitors drives increased autophagic flux in PDAC cells to facilitate survival224,225”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [224] Kinsey, 2019, Protective autophagy elicited by RAF-->MEK-->ERK inhibition suggests a treatment strategy for RAS-driven cancers, Nat. Med. source
- Not checked yetcites [225] Garrido, 2016, The urgent need to recover MHC class I in cancers for effective immunotherapy, Curr. Opin. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Directly targeting glycolysis through lactate dehydrogenase inhibition has shown mixed results depending on p53 status58”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [58] Rajeshkumar, 2015, Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function, Cancer Res. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“recent studies have shown that the use of DON or analogs in murine PDAC models also appear to have immunomodulatory effects204,205”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [204] Sharma, 2020, Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy, J. Clin. Invest. source
- Not checked yetcites [205] Perera, 2015, Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism, Nature source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Major histocompatibility complex I (MHC-I) down-regulation is a major mechanism by which cancer cells escape detection by the immune system226”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [226] Yamamoto, 2020, Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The exchange of alanine and other non-essential amino acids from fibroblasts to promote PDAC metabolism is linked to both autophagy and macropinocytosis in the fibroblasts248,249”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [248] Zhang, 2021, Macropinocytosis in cancer-associated fibroblasts is dependent on CaMKK2/ARHGEF2 signaling and functions to support tumor and stromal cell fitness, Cancer Discov. source
- Not checked yetcites [249] Kerk, 2022, Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context, eLife source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“TAMs and other anti-inflammatory macrophages release numerous pyrimidine species that are avidly consumed by PDAC cells258.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [258] Dalin, 2019, Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance, Cancer Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“PDAC cells can utilize macropinocytosis to obtain proline from CAF produced collagen230.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [230] Commisso, 2013, Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“PDAC cell lines classified by bioenergetic preferences and response to metabolic inhibitors revealed “glycolytic”, “lipogenic”, and “slow proliferating” metabolic subtypes238”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [238] Halbrook, 2022, Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells, Nat. Cancer source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Pancreatic CAFs are in close proximity to PDAC cells147.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [147] Biffi, 2019, IL1-induced JAK/STAT signaling is antagonized by TGFbeta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma, Cancer Discov. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“Examination of metabolic exchange between pancreatic CAFs and cancer cells revealed that alanine is selectively released by fibroblasts and consumed by PDAC cells248.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [248] Zhang, 2021, Macropinocytosis in cancer-associated fibroblasts is dependent on CaMKK2/ARHGEF2 signaling and functions to support tumor and stromal cell fitness, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The programming of TAMs is mediated by oncogenic-KRAS reprogramming of PDAC cells.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [260] Van de Velde, 2017, T cells encountering myeloid cells programmed for amino acid-dependent immunosuppression use Rictor/mTORC2 protein for proliferative checkpoint decisions, J. Biol. Chem. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the exchange of metabolites such as pyruvate can be used by PDAC cells to maintain redox balance250.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [250] Zhao, 2016, Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism, eLife source
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“pancreatic tumor-initiating cells have been found to preferentially utilize mitochondrial metabolism, as compared to glycolytic metabolism preferred by bulk tumor cells244.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [244] Elgogary, 2016, Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer, Proc. Natl. Acad. Sci. USA source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“PDAC cells that survive withdrawal of oncogenic KRAS signaling exhibit a targetable dependence on mitochondrial metabolism68.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [68] Viale, 2014, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“metabolic characterization of clonal lines isolated from tumors revealed that two distinct populations can co-exist within the same tumor239”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [239] Recouvreux, 2020, Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer, J. Exp. Med. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“PDAC program CAFs to engage a BCAT1-driven metabolic program, leading to CAF production of branched-chain α-ketoacid precursors reciprocally exchanged to fuel PDAC metabolism255.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [255] Campbell, 2021, Glutamine deprivation triggers NAGK-dependent hexosamine salvage, eLife source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Targeting TXNIP can reverse the metabolic and epigenetic programming identified to be unique in metastatic PDAC.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“extracellular asparagine from serum and produced by a constitutively active integrated stress response in subpopulations of PDAC cells can be targeted using asparaginase, potently sensitizing PDAC tumors to mitochondrial inhibition in pre-clinical models239,246.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Differential expression of solute carrier proteins (SLCs) can also function to promote a one-way fibroblast-SLC1A4 / PDAC-SLC38A2 exchange axis, enabling the exchange of alanine253.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [253] Auciello, 2019, A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Lactate produced from upregulated glycolysis in PDAC cells combines with GM-CSF, released in a KRAS-dependent fashion, to stimulate macrophage polarization260.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [260] Van de Velde, 2017, T cells encountering myeloid cells programmed for amino acid-dependent immunosuppression use Rictor/mTORC2 protein for proliferative checkpoint decisions, J. Biol. Chem. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The differential metabolism of these regions can be readily observed through imaging techniques236,237, including spatial heterogeneity of glycolysis.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [236] Kishimoto, 2019, Imaging of glucose metabolism by 13C-MRI distinguishes pancreatic cancer subtypes in mice, eLife source
- Not checked yetcites [237] Daemen, 2015, Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors, Proc. Natl. Acad. Sci. USA source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Activation of CAFs from quiescent stellate cells engages a metabolic program supporting the secretion of several lipid species.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“extracellular matrix produced by stromal fibroblasts and PDAC cells can serve as a fuel for PDAC metabolism.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“CAFs provide signals that promote epigenetic and metabolic re-wiring of cancer cell metabolism247.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [247] Sousa, 2016, Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Stellate cell-derived exosomes have been shown to carry numerous metabolite and protein cargo to pancreatic cancer cells, including amino acids251,252.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [251] Raghavan, 2022, NetrinG1(+) cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress, Cancer Res Commun. source
- Not checked yetcites [252] Parker, 2020, Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer, Cancer Discov. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Among these lysophosphatidylcholines are hydrolyzed by autotaxin released from cancer cells to provide the potent signaling molecule lysophosphatidic acid, which promotes PDAC proliferation and migration254”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [254] Zhu, 2020, Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours, Nat. Metab. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these studies highlight the heterogeneity of metabolic features and behaviors utilized by PDAC cells extend beyond simple re-wiring of anabolic and catabolic pathways.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“both TAM and CAF-released deoxycytidine act to inhibit the efficacy of gemcitabine through molecular competition at deoxycytidine kinase258,259”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [258] Dalin, 2019, Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance, Cancer Res. source
- Not checked yetcites [259] Boyer, 2022, Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway, eLife source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Glutamine deprivation promotes an epithelial-to-mesenchymal transition (EMT) through the upregulation of the master EMT regulator Slug240, enabling PDAC metastasis to the lung.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [240] McDonald, 2017, Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis, Nat. Genet. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This re-wired metabolic pathway revealed a dependence on a unique pentose conversion pathway, centered on the upregulated activity of phosphogluconate dehydrogenase (PGD)242.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [242] Bechard, 2020, Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis, Nat. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The disparity between nutrient availability imposed by the pancreatic TME, the bloodstream and other routes of dissemination, and secondary organs colonized in metastasis allow for varied metabolic states for PDAC cells194.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [194] Guillaumond, 2013, Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma, Proc. Natl. Acad. Sci. USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Deoxycytidine can also be released from CAFs259”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [259] Boyer, 2022, Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway, eLife source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“PDAC cells can also obtain GlcNAC through N-acetylglucosamine kinase salvage from matrix components256, including hyaluronic acid257”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Comparison of the epigenetic and metabolic state of primary vs. metastatic PDAC patient tumors revealed the upregulation of anabolic glucose metabolism with a concurrent dependence on the oxidative pentose phosphate pathway during the evolution of metastasis241.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [241] Bechard, 2018, Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases, Oncogene source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“asparagine produced by subpopulations of PDAC cells that have a constitutively active integrated stress response support the mitochondrial metabolism of other PDAC cells during limited respiration239, providing a barrier to metabolic targeting.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [239] Recouvreux, 2020, Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer, J. Exp. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CyTOF and scRNA-seq of isolated cell populations from PDAC tissue has provided an unprecedented depth of knowledge on the complexity and heterogeneity of the TME.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Neurons can also provide serine that functions to support mRNA translation in PDAC263”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [263] Pushalkar, 2018, The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“scRNA-seq datasets from human and murine tumors have identified multiple unique neoplastic epithelial populations within individual tumors149,269, which represent multiple PDAC subtypes within the same tumor270.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [149] Dominguez, 2020, Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy, Cancer Discov. source
- Not checked yetcites [269] Lee, 2021, Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single-cell transcriptomics in Real-world pancreatic cancer biopsies, Clin. Cancer Res. source
- Not checked yetcites [270] Monberg, 2022, Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution, Nat. Commun. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The polarization of TAMs occurs through a PI3K-AKT pathway, activating ACLY signaling and the expression of the arginine catabolic enzyme Arginase 1 (Arg1).”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [260] Van de Velde, 2017, T cells encountering myeloid cells programmed for amino acid-dependent immunosuppression use Rictor/mTORC2 protein for proliferative checkpoint decisions, J. Biol. Chem. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Illustrating this, a 36 marker CyTOF characterization of peripheral blood from PDAC patients revealed neoadjuvant FOLFIRINOX promotes an increase in effector T cells and concurrent decrease in suppressive immune populations268.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [268] Hosein, 2019, Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution, JCI Insight source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“suggesting that representation of the in vivo biology of the original tumor is not stable in culture.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [137] Raghavan, 2021, Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer, Cell source
- Not checked yetcites [271] Schalck, 2022, Single-cell sequencing reveals trajectory of tumor-infiltrating lymphocyte states in pancreatic cancer, Cancer Discov. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“anti-inflammatory macrophages and pancreatic TAMs utilize a predominantly mitochondrial bioenergetic metabolic programming, fueled by fatty acid metabolism258.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [258] Dalin, 2019, Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance, Cancer Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“In fact, PDAC cell lines and patient-derived organoid cultures demonstrate multiple, distinct, sub-populations by scRNA-seq271, highlighting epithelial cell heterogeneity even in ex vivo models.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [271] Schalck, 2022, Single-cell sequencing reveals trajectory of tumor-infiltrating lymphocyte states in pancreatic cancer, Cancer Discov. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The use of mass cytometry comparing millions of cells isolated from 19 murine PDAC tumors against library of 40+ known fibroblast and mesenchymal cell markers was integral to the discovery of CD105 as a key indicator of tumor promoting/tumor suppressive fibroblast behavior152.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [152] Krishnamurty, 2022, LRRC15(+) myofibroblasts dictate the stromal setpoint to suppress tumour immunity, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent advances in spatial profiling technologies have also allowed the newer platforms to approach true single cell, and even subcellular, resolution280.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [280] Rahib, 2016, Evaluation of pancreatic cancer clinical trials and benchmarks for clinically meaningful future trials: A systematic review, JAMA Oncol. source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The advancement of single-cell analysis technologies and high-dimensional spatial analysis techniques have rapidly broadened our understanding of PDAC.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Parallel use of spatial and isolated single-cell analysis techniques has proven adept at identification of interactions between cell types in the TME.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“lactate produced by cancer cells in hypoxic regions can be used to fuel PDAC cells in well oxygenated areas195.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [195] Boudreau, 2016, Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition, Nat. Chem. Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, the spatial organization of cell populations also has a central role in shaping their relationships and phenotypes.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“bacterial and fungal pathogens can infiltrate into PDAC264–266.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [264] Aykut, 2019, The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL, Nature source
- Not checked yetcites [265] Riquelme, 2019, Tumor microbiome diversity and composition influence pancreatic cancer outcomes, Cell source
- Not checked yetcites [266] Geller, 2017, Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Not surprisingly, therefore, the first clinical hints of success at deploying immunotherapy in PDAC have thus come from regimens that combine chemotherapy with targeting of one or more additional nodes within the dysfunctional TME (myeloid cells, Tregs) in combination with immune checkpoint inhibitors286,287.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [286] Bockorny, 2021, Motixafortide and pembrolizumab combined to nanoliposomal irinotecan, fluorouracil, and folinic acid in metastatic pancreatic cancer: the COMBAT/KEYNOTE-202 trial, Clin. Cancer Res. source
- Not checked yetcites [287] Winograd, 2015, Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma, Cancer Immunol. Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, combined scRNA-seq, multiplex IHC, and CyTOF immune profiling demonstrated an inverse correlation between suppressive myeloid populations and CD8 effector T cell infiltrations277.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [277] Freed-Pastor, 2021, The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer, Cancer Cell source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This underappreciated level of complexity spans populations of stromal cells, immune cells, and distinct populations of cancer cells that co-exist within individual tumors.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“gammaproteobacterial PDAC have been shown to directly detoxify gemcitabine through expression of cytidine deaminase267.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [267] Peng, 2021, Neoadjuvant FOLFIRINOX therapy is associated with increased effector T cells and reduced suppressor cells in patients with pancreatic cancer, Clin. Cancer Res. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Illustrating the utility of this approach, multiplexed myeloid, lymphoid, and functional antibody panels were able to spatially define the relationship between myeloid and T cell populations in PDAC patient tissue275.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [275] Kiemen, 2022, CODA: quantitative 3D reconstruction of large tissues at cellular resolution, Nat. Methods source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A common thread emerging from these cutting-edge studies is that the levels of heterogeneity that can exist within PDAC tumors extend far beyond what has previously been described.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
In the paper
“The data gained through this approach suggests neoadjuvant treated patients would potentially respond better to adjuvant immunotherapy.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [268] Hosein, 2019, Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution, JCI Insight source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Arginase-mediated arginine depletion by myeloid cells is a metabolic mediator of immune suppression through limitation of arginine to cytotoxic T cells, which impairs their activity261.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [261] Liebl, 2014, The impact of neural invasion severity in gastrointestinal malignancies: a clinicopathological study, Ann. Surg. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Fortunately, advances in multiplexed immunohistochemical staining and imaging technology have enabled the expansion of markers that can be used in spatial assessment of cancer cell number, function and evolutionary trajectories273,274.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [273] Seferbekova, 2022, Spatial biology of cancer evolution, Nat. Rev. Genet.
- Not checked yetcites [274] Liudahl, 2021, Leukocyte heterogeneity in pancreatic ductal adenocarcinoma: phenotypic and spatial features associated with clinical outcome, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“For example, it is now evident that simply combining two “off the shelf” immune checkpoint inhibitors to enhance effector T cell function – a strategy that has worked in several other solid cancers – has minimal to no impact in a disease where a multiplicity of immune defects co-exist283,284.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [283] Brahmer, 2012, Safety and activity of anti-PD-L1 antibody in patients with advanced cancer, N. Engl. J. Med. source
- Not checked yetcites [284] Gulhati, 2023, Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer, Nat. Cancer
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In line with these observations, subsequent studies using murine PDAC models have further implicated the CD155/TIGIT axis as a potential target to move forward to clinical trials to enhance immunotherapy278.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [278] Hwang, 2022, Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment, Nat. Genet. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Many of the recent promising clinical signals in PDAC have arisen through rigorous preclinical analyses in syngeneic and autochthonous models that predated the trial and informed its design288.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [288] Catenacci, 2015, Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer, J. Clin. Oncol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In fact, partly driven by the challenging trajectory of “conventional” drug development in PDAC, there has been an evolving shift from large, empirical trials towards those that are focused on fewer patient numbers, but which feature in-depth correlative studies that provide insights into mechanisms of response and resistance184,292,293.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [184] Byrne, 2021, Neoadjuvant Selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer, Clin. Cancer Res. source
- Not checked yetcites [292] Knox, 2022, PASS-01: pancreatic adenocarcinoma signature stratification for treatment–01, J. Clin. Oncol. source
- Not checked yetcites [293] Picozzi, 2022, Precision Promise (PrP): an adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC), J. Clin. Oncol. source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“An unfortunate example of this pertains to the trials of hyaluronic acid targeted therapies in patients with advanced PADC, which used dosages that were three orders of magnitude lower than what garnered improved survival in animal models291.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [291] Balachandran, 2022, Phase I trial of adjuvant autogene cevumeran, an individualized mRNA neoantigen vaccine, for pancreatic ductal adenocarcinoma, J. Clin. Oncol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, approaches that encompass as many of these features as possible present the highest likelihood of success.”
§ Pancreatic Cancer: Advances and Challenges > Summary:
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Among common solid cancers, PDAC is among the most frequent to fail Phase 3 trials.
- Rests on an assumption: A treatment's clinical success depends critically on the underlying tumor biology.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Even rigorously conducted preclinical studies are not predictive of success upon subsequent clinical translation if they deviate significantly from the preclinical “recipe”.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 81
- Probably not a substantial claim. 10
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“MyCAFs are localized close to the neoplastic cells and thought to be responsible for deposition of extracellular matrix, whereas iCAFs tend to occupy spaces between islands of the PDAC cells and release IL6 and other anti-inflammatory cytokines.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Partly supportedcites [147] Biffi, 2019, IL1-induced JAK/STAT signaling is antagonized by TGFbeta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma, Cancer Discov. sourceExperimental — accuracy not yet measured
The Introduction says myCAFs lie adjacent to tumor cells while iCAFs are farther away in the dense stroma; the Discussion attributes extracellular-matrix deposition to myCAFs. The Results identify IL-6 among factors secreted by iCAFs, but describe their profile as inflammatory, not anti-inflammatory. The paper does not specifically locate iCAFs between PDAC cell islands. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
In the paper
“Patients progressing on first-line regimens can be offered the possibility of switching to the other regimen, or a second-line regimen that includes a liposomal formulation of irinotecan in combination with 5-FU10, provided they have not received either of these agents previously.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [10] Wang-Gillam, 2016, Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial, Lancet source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“PDAC accounts for greater than 90% of pancreas cancers and has a distinct molecular profile and natural history from pancreatic neuroendocrine tumors”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [22] de Wilde, 2012, Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy, Nat. Rev. Gastroenterol. Hepatol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“almost three-fourths of patients who were diagnosed with PDAC on active surveillance had Stage I disease, and an equal proportion were still alive at five years”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [21] Dbouk, 2022, The multicenter cancer of pancreas screening study: impact on stage and survival, J. Clin. Oncol. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“two new combination regimens have emerged as the first-line therapy in patients with advanced PDAC. The first is a combination of 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin, which carries the acronym FOLFIRINOX. The second is the combination of gemcitabine and an albumin nanoparticle conjugate of paclitaxel (nab-paclitaxel)8,9.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“current guidelines advise against screening the general population and instead emphasize biomarker studies be focused on well-defined high-risk cohorts44.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [44] Owens, 2019, Screening for pancreatic cancer: US Preventive Services Task Force reaffirmation recommendation statement, JAMA source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“a remarkable 80% of patients who present with the lowest stages of PDAC (Stage IA or IB disease) were alive at five years, compared to less than 10% of patients with advanced disease19.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Treatment Strategies for Pancreatic Ductal Adenocarcinoma
What the sources say
- Not checked yetcites [19] Blackford, 2020, Recent trends in the incidence and survival of stage 1A pancreatic cancer: A surveillance, epidemiology, and end results analysis, J. Natl. Cancer Inst. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Patients with Stage IA/IB PDAC are typically diagnosed incidentally and make up no more than 3–5% of cases.
In the paper
“cystic mucinous neoplasms of the pancreas, of which intraductal papillary mucinous neoplasms (IPMNs) are the most common histological subtype, are macroscopic precursors that arise within the main pancreatic duct or one of its branches. These can be observed and followed for progression by imaging techniques25.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [25] Matthaei, 2011, Cystic precursors to invasive pancreatic cancer, Nat. Rev. Gastroenterol. Hepatol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Pancreatic Intraepithelial Neoplasia (PanINs) are the most frequently observed precursor lesions and are, by definition, microscopic lesions that cannot be observed on abdominal imaging scans24.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Precursor Lesions of Pancreatic Cancer: An Opportunity for Early Detection
What the sources say
- Not checked yetcites [24] Overbeek, 2016, Surveillance for neoplasia in the pancreas, Best Pract. Res. Clin. Gastroenterol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“KRAS mutations are observed in most low-grade PanINs and IPMNs, suggesting KRAS is the initiating genetic event driving exocrine neoplasia46,47.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [46] Kanda, 2012, Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia, Gastroenterology source
- Not checked yetcites [47] Fujikura, 2021, Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions, Gut source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“deletion of KDM6A results in accelerated tumorigenesis and acquisition of an aggressive transcriptional subtype95–97.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [95] Kalisz, 2020, HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer, EMBO J. source
- Not checked yetcites [96] Yi, 2022, KDM6A regulates cell plasticity and pancreatic cancer progression by noncanonical activin pathway, Cell. Mol. Gastroenterol. Hepatol. source
- Not checked yetcites [97] Andricovich, 2018, Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“altered p53 function has a multitude of tumor-promoting effects on neoplastic cells, including increased genomic instability30, reprogrammed cellular metabolism57,58, and enhanced metastatic propensity59.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [30] Hingorani, 2005, Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice, Cancer Cell source
- Not checked yetcites [57] Morris, 2019, alpha-Ketoglutarate links p53 to cell fate during tumour suppression, Nature source
- Not checked yetcites [58] Rajeshkumar, 2015, Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function, Cancer Res. source
- Not checked yetcites [59] Weissmueller, 2014, Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“a pivotal clinical trial in patients with PDAC and germline BRCA1/2 mutations established the benefit of administering an orally bioavailable PARP inhibitor on improved progression free survival (PFS). This led to the approval of targeted therapy in this setting87.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [87] Golan, 2019, Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, N. Engl. J. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Mutations of ATM are the second most frequent known cause of germline mutations in PDAC, after BRCA2, conferring a comparable lifetime increased risk of PDAC in mutation carriers91.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [91] Hsu, 2021, Risk of pancreatic cancer among individuals with pathogenic variants in the ATM gene, JAMA Oncol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the first published clinical series of KRASG12C inhibitor monotherapy in advanced PDAC, responses occurred in a minority of patients (~21%) and were generally transient75.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [75] Strickler, 2023, Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer, N. Engl. J. Med. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Interferon cluster loss creates a “cold” tumor immune milieu and resistance to immunotherapy52”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [52] Barriga, 2022, Machete identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis, Nat. Cancer source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: CDKN2A is often lost by homozygous deletions at chromosome 9p21, which is associated with codeletions of a neighboring interferon cluster in half of cases.
In the paper
“the KRASG12C allele occurs in only 1.6% of PDAC cases, whereas the KRASG12D allele is present in greater than 40%, followed in frequency by KRASG12V and KRASG12R mutations74.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [74] Waters, 2018, KRAS: the critical driver and therapeutic target for pancreatic cancer, Cold Spring Harb. Perspect. Med. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Chromatin remodeling and SWI/SNF complex genes are one of the most frequently altered class of genes in PDAC45,48–50, and can occur via somatic deletions of the associated chromosomal loci94.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Genomic Drivers of Pancreatic Cancer
What the sources say
- Not checked yetcites [45] 2017, Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma, Cancer Cell source
- Not checked yetcites [48] Jones, 2008, Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science source
- Not checked yetcites [49] Waddell, 2015, Whole genomes redefine the mutational landscape of pancreatic cancer, Nature source
- Not checked yetcites [50] Bailey, 2016, Genomic analyses identify molecular subtypes of pancreatic cancer, Nature source
- Not checked yetcites [94] Shain, 2012, Convergent structural alterations define SWItch/Sucrose nonfermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer, Proc. Natl. Acad. Sci. USA source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Mauer et al., found isolated epithelial tissues supported the Moffitt “classical” or “basal-like” subtypes, while they found no evidence of the Bailey “ADEX” subtype or Collisson “exocrine-like” subtypes in epithelial enriched tumor samples132.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [132] Maurer, 2019, Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes, Gut source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“these subtypes could predict drug response in cell culture models, and patient outcomes were significantly different across their subtypes.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [130] Collisson, 2011, Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy, Nat. Med. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Deletion of the ductal progenitor gene Sox9 prevented KRAS-driven transformation, while Sox9 overexpression accelerated PanIN development.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Cell-of-Origin: An Unsettled Debate
What the sources say
- Not checked yetcites [118] Kopp, 2012, Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“samples “ADEX” or “exocrine-like” signatures are associated with low PDAC cellularity45, suggesting these signals derive from stromal/immune/non-cancerous elements of tissues.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [45] 2017, Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma, Cancer Cell source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Moffit and colleagues devised a “virtual dissection strategy” to computationally subtract the transcriptional background imposed by stromal and immune cells from bulk-RNA sequencing signatures131. Using this approach, they identified two subtypes of PDAC tumors, termed “classical” and “basal-like”, in addition to two stromal subtypes termed “normal stroma” and “activated stroma”.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [131] Moffitt, 2015, Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma, Nat. Genet. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“they suggested that their findings demonstrate that the Bailey ADEX subtype is likely contamination of pancreatic acinar cells.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [133] Puleo, 2018, Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features, Gastroenterology source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“consensus has best coalesced around two major subtypes, classical and basal-like, with some populations showing mixed features135”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [135] Collisson, 2019, Molecular subtypes of pancreatic cancer, Nat. Rev. Gastroenterol. Hepatol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Fibroblasts represent the most abundant cell type in the TME and are largely responsible for the deposition of the extracellular matrix driving the characteristic physiological properties of PDAC140”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“several candidate regulators such as TP63136, which can be induced by KDM6A loss97, can promote more aggressive subtypes”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [136] Somerville, 2018, TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma, Cell Rep. source
- Not checked yetcites [97] Andricovich, 2018, Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“They identified five different subtypes of PDAC tumors: “basal-like-A”, “basal-like-B”, “hybrid”, “classical-A” and “classical-B”.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [134] Chan-Seng-Yue, 2020, Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution, Nat. Genet. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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The quote only partly states this claim.
In the paper
“They reported best overlap with the Moffitt subtypes, and their resolution allowed for subclassification of both, while their hybrid subtype did not consistently fall into previously reported classes.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Transcriptional Subtypes of Human Pancreatic Cancer
What the sources say
- Not checked yetcites [134] Chan-Seng-Yue, 2020, Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution, Nat. Genet. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the transcriptional profiles of apCAFs overlap with mesothelial cells150, and based on lineage tracing studies in mice have been postulated to derive from a mesothelial origin145”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [150] Feig, 2013, Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer, Proc. Natl. Acad. Sci. USA source
- Not checked yetcites [145] Han, 2023, The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis, Nat. Commun. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CD40 agonists to reprogram macrophages to a less immunosuppressive status, leading to CD8 T cell infiltration that would drive the conversion from a “cold” to a “hot tumor”183”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [183] Padrón, 2022, Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial, Nat. Med. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“targeting MDSCs and/or TAMs improves adaptive immune responses in mouse models of pancreatic cancer and can potentiate checkpoint inhibition approaches176,177,179,180”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [176] Pylayeva-Gupta, 2012, Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia, Cancer Cell source
- Not checked yetcites [177] Zhu, 2017, Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression, Immunity source
- Not checked yetcites [179] Candido, 2018, CSF1R(+) macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype, Cell Rep. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Depletion of these fibroblasts, or targeting of CXCL12, sensitizes PDAC to immune checkpoint blockade in preclinical models151”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [151] Hutton, 2021, Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the specific nature of the sub-TME in an individual tumor did not predict outcome, but higher sub-TME heterogeneity was a poor prognostic sign”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“PDAC cells produce “tonic” (low) levels of a distinct oncogenic homo-trimeric collagen that binds to α3β1 integrin, thereby mediating immune suppression and reprogramming the tumor-associated microbiome167”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [167] Aguilera, 2017, Inhibition of discoidin domain Receptor 1 reduces collagen-mediated tumorigenicity in pancreatic ductal adenocarcinoma, Mol. Cancer Ther. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Focal adhesion kinase (FAK), hyperactivated in pancreatic cancer cells, is an important driver of fibrosis and immune suppression in the TME174”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [174] Lander, 2022, Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“FAK inhibition was shown to markedly reduced fibrosis and decreased the infiltration of tumor-promoting immune cells in mice.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CAFs expressing Fibroblast Activation Protein (FAP) also express high levels of CXCL12 and inhibit tumor T cell infiltration.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [151] Hutton, 2021, Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Dendritic cells (DCs) are found in low numbers in PDAC, as compared to other tumor types, and the DCs present are of poor quality for antigen presentation186”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [186] Byrne, 2016, CD40 stimulation obviates innate sensors and drives T cell immunity in cancer, Cell Rep. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The majority of collagen is type I collagen164, largely generated by CAFs147,165”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [164] Hosein, 2020, Pancreatic cancer stroma: an update on therapeutic targeting strategies, Nat. Rev. Gastroenterol. Hepatol. source
- Not checked yetcites [147] Biffi, 2019, IL1-induced JAK/STAT signaling is antagonized by TGFbeta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma, Cancer Discov. source
- Not checked yetcites [165] Chen, 2021, Type I collagen deletion in alphaSMA(+) myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Oncogenic KRAS signaling drives expression of granulocyte colony stimulating factor (GM-CSF) by PDAC cells, promoting recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs)176,177”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [176] Pylayeva-Gupta, 2012, Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia, Cancer Cell source
- Not checked yetcites [177] Zhu, 2017, Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression, Immunity source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Hyaluronic acid is a glycosaminoglycan polymer, thought to be released by predominantly by CAFs, that avidly retains water and promotes the characteristically high interstitial fluid pressure found in pancreatic tumors140”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Targeted deletion of type I collagen from SMA-expressing fibroblasts increases immune suppressive myeloid infiltration, accelerating tumor progression166”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [166] Chen, 2022, Oncogenic collagen I homotrimers from cancer cells bind to alpha3beta1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Early efforts to identify and understand different CAF populations identified a myofibroblast-like population (myCAF) and an inflammatory fibroblast population (iCAF)147”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [147] Biffi, 2019, IL1-induced JAK/STAT signaling is antagonized by TGFbeta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma, Cancer Discov. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“CAFs are largely responsible for deposition of the dense extracellular matrix found in PDAC, largely consisting of collagen and hyaluronic acid.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“novel agonists developed in PDAC models to target the CD11b/CD18 receptor present on most tumor-infiltrating myeloid subsets have shown promising pre-clinical data, currently being tested in the clinic181,182”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“fibroblasts expressing leucine-rich-repeat-containing protein 15 (LRRC15) were identified in mouse PDAC but not in the normal pancreas, and these fibroblasts are postulated to promote tumor growth and inhibit anti-tumor immune responses153”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [153] Shaashua, 2022, BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling, Nat. Commun. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“FAK inhibition-mediated reprogramming of the stroma was shown to overcome radiation resistance and sensitize the tumors to immunotherapy175”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [175] Bayne, 2012, Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer, Cancer Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Examples include the non-oxidative pentose phosphate pathway, which enables nucleotide biosynthesis, and the hexosamine biosynthesis pathway, which generates GlcNAc required for posttranslational modifications64,195”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Combined pharmacological targeting of MEK or ERK with hydroxychloroquine potently inhibits xenograft tumor growth and has shown efficacy in clinical treatment of PDAC, with additional trials on-going.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“increased biogenesis of lysosomes and constitutive engagement of the autophagy “self-eating” recycling program206”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [206] Yang, 2011, Pancreatic cancers require autophagy for tumor growth, Genes Dev. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Increased expression of NCOA4 accelerates tumorigenesis in mice, and genetic ablation leads to delayed tumor growth that is eventually overcome through development of compensatory iron acquisition pathways216”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [216] Ravichandran, 2022, Coordinated transcriptional and catabolic programs support iron-dependent adaptation to RAS-MAPK pathway inhibition in pancreatic cancer, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Oncogenic Ras also drives glutamine anaplerosis to provide a significant source of carbon for TCA cycle, biosynthesis of glutathione necessary to detoxify reactive oxygen species (ROS), and enables a non-canonical malate-aspartate shuttle to generate NADPH for redox balance198”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [198] Biancur, 2017, Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism, Nat. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“6-Diazo-5-oxo-l-norleucine (DON) was identified as a potential anti-cancer glutamine antagonist more than a half century ago201, but its lack of substrate specificity provided too much off-target toxicity202.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [201] Lynch, 1982, Phase II evaluation of DON (6-diazo-5-oxo-L-norleucine) in patients with advanced colorectal carcinoma, Am. J. Clin. Oncol. source
- Not checked yetcites [202] Rais, 2016, Discovery of 6-Diazo-5-oxo-l-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: A potential treatment for glioblastoma, J. Med. Chem. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“recent advances have optimized DON as a pro-drug with pharmacokinetic properties that increase tumor targeting203, including an orally available analog with promising pre-clinical results in murine PDAC models204”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [203] Leone, 2019, Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion, Science source
- Not checked yetcites [204] Sharma, 2020, Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy, J. Clin. Invest. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“MEK-inhibition in PDAC increased both lysosome biosynthesis and ferritinophagy, necessary to support increased iron-sulfur cluster proteins for respiration217”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [217] Dixon, 2012, Ferroptosis: an iron-dependent form of nonapoptotic cell death, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“MHC-I expression is low at the PDAC cell surface, instead found predominantly localized within autophagosomes and lysosomes227”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [227] Zhu, 2021, Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells, Cell Metab. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Labile iron can also potentiate cell death via the lipid oxidation process known as “ferroptosis”218”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [218] Badgley, 2020, Cysteine depletion induces pancreatic tumor ferroptosis in mice, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“ferritin is trafficked to autophagosomes via nuclear receptor coactivator 4 (NCOA4), and free iron is subsequently released by autophagy through a process termed “ferritinophagy”214”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [214] Pantopoulos, 2012, Mechanisms of mammalian iron homeostasis, Biochemistry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Mutant KRAS drives upregulated glycolysis, not only increasing production of lactate, but also providing key carbon inputs for synthesis of molecules required for proliferation.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This shift in immune infiltration follows a loss of myCAFs upon Treg depletion, as Tregs proved a significant source of TGF-beta.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
What the sources say
- Not checked yetcites [192] Kamphorst, 2015, Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein, Cancer Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Differential activation of the integrated stress response can also be used to define sub-populations within individual tumors, which drives differential sensitivity to metabolic inhibitors239.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [239] Recouvreux, 2020, Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer, J. Exp. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“High glycolytic flux is required to maintain upregulated PGD metabolism, and this in maintained in part through suppression of thioredoxin-interacting protein (TXNIP) transcription243.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [243] Sancho, 2015, MYC/PGC-1alpha balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells, Cell Metab. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“only a subset of PDAC cell lines with mutant KRAS demonstrate a constitutive macropinocytosis program, whereas others engage this process only when challenged with glutamine deprivation235”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
What the sources say
- Not checked yetcites [235] Yamamoto, 2020, Molecular imaging of the tumor microenvironment reveals the relationship between tumor oxygenation, glucose uptake, and glycolysis in pancreatic ductal adenocarcinoma, Cancer Res. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the metabolic milieu in pancreatic tumors is deregulated, with some nutrients being enriched and others depleted.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The glycolytic metabolic subtype aligns with a “quasimesenchymal” transcriptional subtype and lipogenic metabolism state with a “classical” signature130.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [130] Collisson, 2011, Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy, Nat. Med. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“the deoxycytidine released among these pyrimidines inhibits the efficacy of the standard of care chemotherapy gemcitabine, and depletion of myeloid cells in mice sensitizes PDAC tumors to gemcitabine treatment.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [258] Dalin, 2019, Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance, Cancer Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These combine to enable PDAC cells to survive nutrient challenging conditions in the primary tumor and provide metabolic flexibility to enable metastasis.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Pancreatic Cancer Metabolism: Adaptations Present Therapeutic Opportunities
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“metabolic inhibition approaches combined with RAS pathway inhibitors have shown strong pre-clinical data and are currently in clinical trials197,224,225”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Heterogeneity in Pancreatic Cancer
What the sources say
- Not checked yetcites [197] Son, 2013, Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway, Nature source
- Not checked yetcites [224] Kinsey, 2019, Protective autophagy elicited by RAF-->MEK-->ERK inhibition suggests a treatment strategy for RAS-driven cancers, Nat. Med. source
- Not checked yetcites [225] Garrido, 2016, The urgent need to recover MHC class I in cancers for effective immunotherapy, Curr. Opin. Immunol. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Further, patient-derived organoid transcriptional landscape and sub-population proportions shift during passaging137,271”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [137] Raghavan, 2021, Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer, Cell source
- Not checked yetcites [271] Schalck, 2022, Single-cell sequencing reveals trajectory of tumor-infiltrating lymphocyte states in pancreatic cancer, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, addition of contextual factors lacking in such ex vivo culture models can potentially rescue the heterogeneity of the original tumor models and the retain the ability to predict response to therapy137.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [137] Raghavan, 2021, Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer, Cell source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“scRNA-seq data confirmed the existence of multiple CAF populations within human and murine pancreatic tumors and allowed the discovery of apCAFs149.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [149] Dominguez, 2020, Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy, Cancer Discov. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, our increased understanding of the symbiotic support mechanisms of nutrients within the pancreatic TME have already identified several therapeutic opportunities.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Neural invasion is a well-recognized feature of pancreatic tumors, with the severity negatively correlating to prognosis262.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
What the sources say
- Not checked yetcites [262] Banh, 2020, Neurons release serine to support mRNA translation in pancreatic cancer, Cell source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Increased understanding of the biology of PDAC has led to a plethora of clinical trials to improve treatment; however, most have fallen short of expectations.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Among common solid cancers, PDAC is among the most frequent to fail Phase 3 trials.
In the paper
“These further identified that CD8 T cells show indications of systemic exhaustion, and a network analysis of potential checkpoint receptor-ligand pairing suggested TIGIT as a key node of immune-suppression.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [277] Freed-Pastor, 2021, The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer, Cancer Cell source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Integration of multiple scRNA-seq datasets combined with lineage tracing studies demonstrated that ap-CAFs can arise from a mesothelial origin and regulate the expansion of regulatory T cells and immune suppression145.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [145] Han, 2023, The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis, Nat. Commun. source
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This has the dual benefit of tumor shrinkage and acts as an in situ antigen release mechanism to allow for an immune response.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This has led to calls to revamp how drug development is furthered for this disease, and to redefine the thresholds needed for agents to move forward to larger phase trials281,282.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [281] Thota, 2017, Preclinical rationale for the Phase III trials in metastatic pancreatic cancer: is wishful thinking clouding successful drug development for pancreatic cancer?, Pancreas source
- Not checked yetcites [282] O'Reilly, 2019, Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: A Phase 2 randomized clinical trial, JAMA Oncol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: Among common solid cancers, PDAC is among the most frequent to fail Phase 3 trials.
In the paper
“Similarly, the combined use of spatial profiling with single-nucleus RNA sequencing has enabled the interrogation of the response of PDAC to neoadjuvant therapy and identified a treatment-refractory “neural-like” progenitor cell type that escapes standard of care regimens279.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [279] He, 2022, High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging, Nat. Biotechnol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Of note, while many differences in immune infiltration and behavior were found between different patients, this ability to spatially assess these data allowed the observation of widespread heterogeneity in individual patients.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > New Technologies Driving New Insights
What the sources say
- Not checked yetcites [275] Kiemen, 2022, CODA: quantitative 3D reconstruction of large tissues at cellular resolution, Nat. Methods source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these studies demonstrate that targeting metabolism is not as simple as defining metabolic vulnerabilities of the cancer cells, and the metabolic state of PDAC cells is heterogenous within individual tumors.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Metabolic Interactions in the Pancreatic Tumor Immune Microenvironment
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a recent preclinical study, dual therapy against CD8 T cell checkpoints using a 41-BB agonist and LAG-3 inhibitor by itself was ineffectual, and yet when administered with a myeloid cell targeted CXCR1/2 antagonist, the triple regimen led to sustained responses in biologically relevant models285.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [285] O'Hara, 2021, CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study, Lancet Oncol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Subsequently, attempts to inactivate CAFs through sonic hedgehog inhibition proved ineffective in patients289, and preclinical studies that were conducted after the fact pinpointed reasons for this failure159,290.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [289] Özdemir, 2015, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Cancer Cell source
- Not checked yetcites [159] Özdemir, 2014, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Cancer Cell source
- Not checked yetcites [290] Hingorani, 2023, Epithelial and stromal co-evolution and complicity in pancreatic cancer, Nat. Rev. Cancer source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“One notable example of an ultimately unsuccessful but informative clinical paradigm came by way of a series of pre-clinical studies proposing the efficacy of systemic therapy would improve through efforts to penetrate the dense fibrosis and high interstitial pressure promoted by the CAFs in pancreatic tumors140,158.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
What the sources say
- Not checked yetcites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source
- Not checked yetcites [158] Rhim, 2014, Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma, Cancer Cell source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Significant progress has been made in understanding the biology of pancreatic cancer over the past several decades, unfortunately, these have not translated into a breakthrough in clinical care for the majority of patients.”
§ Pancreatic Cancer: Advances and Challenges > Summary:
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Among common solid cancers, PDAC is among the most frequent to fail Phase 3 trials.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While preclinical models remain far from perfect, they do offer valuable insights into potential mechanisms of failure when trials are unsuccessful.”
§ Pancreatic Cancer: Advances and Challenges > Introduction: > Clinical Trials: Setting Expectations for Future Success
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Patients with Stage IA/IB PDAC are typically diagnosed incidentally and make up no more than 3–5% of cases.
“patients with such low stage tumors are typically diagnosed incidentally and comprise no more than 3–5% of cases.”
The paper relies on this without support.
CA19-9 is the most widely used diagnostic biomarker for PDAC but has suboptimal sensitivity in early-stage disease.
“The carbohydrate antigen 19–9 (CA19–9), also known as sialyl-Lewisa, is currently the most widely used diagnostic biomarker for PDAC, although it has a suboptimal sensitivity in early-stage disease.”
The paper relies on this without support.
CDKN2A is often lost by homozygous deletions at chromosome 9p21, which is associated with codeletions of a neighboring interferon cluster in half of cases.
“CDKN2A is often lost by homozygous deletions at the chromosomal 9p21 locus, which is associated with codeletions of a neighboring interferon cluster in half of cases.”
The paper relies on this without support.
Neoplastic cells in PDAC often constitute a minority of the overall cellularity within the tumor.
“The neoplastic cells in PDAC often constitute a minority of the overall cellularity within the tumor.”
The paper relies on this without support.
The aggressive biology, therapy resistance, and heterogeneity of PDAC are driven nearly as much by non-cancerous tumor components as by PDAC cells.
“Indeed, the aggressive biology, resistance to therapy, and heterogeneity of the disease is driven nearly as much by the non-cancerous components of the tumor as the PDAC cells.”
The paper relies on this without support.
Myeloid cell populations make up the largest immune cell population in pancreatic tumors.
“Myeloid cell populations make up the largest immune cell population in pancreatic tumors (Fig. 3).”
The paper relies on this without support.
A lack of infiltration by cytotoxic CD8 T cells is a notable feature of the PDAC tumor microenvironment.
“One of the most notable features of the PDAC TME is the lack of infiltration by cytotoxic CD8 T cells.”
The paper relies on this without support.
Physical barriers in PDAC tumors limit access to blood-derived nutrients and oxygen, leading to dysregulated nutrient profiles and regional hypoxia.
“The physical barriers imposed within PDAC tumors function to limit access to blood-derived nutrients and oxygen, leading to dysregulate nutrient profiles and promote regional hypoxia.”
The paper relies on this without support.
PDAC cells exhibit numerous adaptations that allow them to survive and thrive under the nutrient constraints imposed by the tumor microenvironment.
“PDAC cells exhibit numerous adaptations to not only survive but thrive under the nutrient constraints imposed by the TME.”
The paper relies on this without support.
Neoplastic epithelial cells within PDAC tumors are often vastly outnumbered by stromal and immune cell populations.
“the neoplastic epithelial cells within PDAC tumors are often vastly outnumbered by the stromal and immune cell populations.”
The paper relies on this without support.
The varied localization, motility, and function of stromal and immune cell populations translate to differential nutrient requirements and can lead to tumor-supporting metabolic interactions.
“The varied localization, motility, and function of these different cell populations translate to differential nutrient requirements and can lead to tumor-supporting metabolic interactions.”
The paper relies on this without support.
These symbiotic metabolic interactions fuel PDAC metabolism, promote resistance to chemotherapy, and drive mechanisms of immune suppression.
“These symbiotic interactions fuel PDAC metabolism, promote resistance to chemotherapy, and drive mechanisms of immune suppression (Figure 4b).”
The paper relies on this without support.
Among common solid cancers, PDAC is among the most frequent to fail Phase 3 trials.
“In fact, PDAC suffers from one of the highest rates of Phase 3 failures amongst common solid cancers.”
The paper relies on this without support.
A treatment's clinical success depends critically on the underlying tumor biology.
“The indelible lessons we continue to learn are that the past is prologue and that the underlying biology remains one of the most pivotal arbitrators of meaningful success in the clinic.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Clinical care for these patients is through systemic chemotherapy, with the first lines of therapy being gemcitabine (GEM), GEM plus nab‐paclitaxel or FOLFIRINOX [5].”
From Pyrvinium Pamoate Alone and With Gemcitabine Exhibits Anti‐Pancreatic Cancer Activity in 2D and 3D Cell Culture Models (2024) · cites this paper as [5]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“three in four PDAC patients develop recurrence within 2 years after resection”
From Pyrvinium Pamoate Alone and With Gemcitabine Exhibits Anti‐Pancreatic Cancer Activity in 2D and 3D Cell Culture Models (2024) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“suggesting that even the small proportion of patients who undergo surgical resection harbour micro‐metastasis [5]”
From Pyrvinium Pamoate Alone and With Gemcitabine Exhibits Anti‐Pancreatic Cancer Activity in 2D and 3D Cell Culture Models (2024) · cites this paper as [5]
In the citing paper
“Context-specific tumor suppressive or oncogenic functions of SWI/SNF chromatin regulation was noticed in PDAC64,65.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [64]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Pancreatic Cancer: Advances and Challenges > Introduction: > The Pancreatic Cancer Tumor Microenvironment
“Oncogenic KRAS signaling drives expression of granulocyte colony stimulating factor (GM-CSF) by PDAC cells, promoting recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs)176,177.”
§ Pancreatic Cancer: Advances and Challenges > References
“Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer.”
Citations
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Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
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Self-citation
Cited by
Sorted by citations
Liquid biopsy in cancer: current status, challenges and future prospects
Ma, L., Guo, H., Zhao, Y., Liu, Z., Wang, C., Bu, J., Sun, T., & Wei, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02021-w · Cited by 820
Lactate and lactylation in cancer
Chen, J., Huang, Z., Chen, Y., Tian, H., Chai, P., Shen, Y., Yao, Y., Xu, S., Ge, S., & Jia, R. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02082-x · Cited by 545
Li, F., Si, W., Xia, L., Yin, D., Wei, T., Tao, M., Cui, X., Yang, J. P., Hong, T., & Wei, R. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02008-9 · Cited by 403
IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer
Caronni, N., Terza, F. L., Vittoria, F. M., Barbiera, G., Mezzanzanica, L., Cuzzola, V., Barresi, S., Pellegatta, M., Canevazzi, P., Dunsmore, G., et al. (2023) · Nature · doi:10.1038/s41586-023-06685-2 · Cited by 418
A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer
Wei, D., Wang, L., Zuo, X., Maitra, A., & Bresalier, R. S. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-2098 · Cited by 177
Self-citation
Metadata
- Authors
- Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A.
- Affiliations
- University of California, Irvine (US)
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2023-04
- Volume
- 186
- Issue
- 8
- Pages
- 1729-1754
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC10182830
- OpenAlex
- W2182290275
- Semantic Scholar
- 496404429708b3fc52539eb23367c22c672de867
- Cited by
- 1,321
- References
- 302
- Citations by year
- 2026: 406 · 2025: 476 · 2024: 358 · 2023: 81
- FWCI
- 43.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Institutes of Health (1r01ca264843-01a1)
- National Cancer Institute (R01-CA264843, P50CA221707, R01CA248160, R01CA220236, R01CA244931, R00CA241357, P30CA046592, U54CA274371, P30CA062203, U01CA274154, R01CA271510, R37CA237421, R01CA260752, U24CA274274, U01CA200468)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- pancreatic ductal adenocarcinoma, tumor microenvironment, cancer metabolism, tumor progression, clinical translation, survival
- MeSH terms
- Humans, Pancreatic Neoplasms, Prognosis, Carcinoma, Pancreatic Ductal, Early Diagnosis, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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