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Cited by 1,321Pancreatic and Hepatic Oncology ResearchPancreatitis Pathology and TreatmentPancreatic function and diabetes

Pancreatic cancer: Advances and challenges

Open access
Halbrook, Christopher J., Lyssiotis, Costas A., Pasca di Magliano, Marina, Maitra, Anirban·2023·Cell
DOI 10.1016/j.cell.2023.02.014PMC PMC10182830
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Abstract

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.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2023.02.014

Cites

301 of 301 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    Patients with major or complete pathological response to neoadjuvant therapy have significantly improved overall survival.

    “patients whose PDAC exhibits a major or complete pathological response to neoadjuvant therapy demonstrate significantly improved overall survival17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Cloyd, 2017, Association of clinical factors with a major pathologic response following preoperative therapy for pancreatic ductal adenocarcinoma, JAMA Surg. source

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  • Premisecitation

    Nearly three of four patients who undergo surgical resection for PDAC develop recurrence within two years.

    “nearly 3 in 4 of patients will develop recurrence within two years”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Groot, 2018, Patterns, timing, and predictors of recurrence following pancreatectomy for pancreatic ductal adenocarcinoma, Ann. Surg. source

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  • Premisecitation

    Many circulating tumor-derived analytes (proteins, autoantibodies, metabolites, DNA, non-coding RNAs, extracellular vesicles) have been assessed for PDAC early detection.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Chari, 2015, Early detection of sporadic pancreatic cancer: summative review, Pancreas source

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    • cites [40] Singhi, 2021, Early detection of pancreatic cancer using DNA-based molecular approaches, Nat. Rev. Gastroenterol. Hepatol. source

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    • cites [41] Pereira, 2020, Early detection of pancreatic cancer, Lancet Gastroenterol. Hepatol. source

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  • Premisecitation

    Approximately 85-90% of PDAC cases are ascribed to arise from PanIN lesions, with the remaining 10-15% from cystic precursors.

    “Approximately 85–90% of PDAC cases are ascribed to originate on the backdrop of PanIN lesions, the remaining 10–15% in cystic precursors20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Singhi, 2019, Early detection of pancreatic cancer: opportunities and challenges, Gastroenterology source

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  • Premisecitation

    For most PDAC patients, no single attributable risk factor is identified outside the 10-15% of cases linked to germline mutations or known risk factors.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Petersen, 2016, Familial pancreatic cancer, Semin. Oncol. source

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    Premisecitation

    Patients progressing on first-line PDAC therapy may receive the other regimen or a second-line regimen containing liposomal irinotecan plus 5-FU if they have not previously received those agents.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PDAC accounts for more than 90% of pancreas cancers and has a distinct molecular profile and natural history from pancreatic neuroendocrine tumors.

    “PDAC accounts for greater than 90% of pancreas cancers and has a distinct molecular profile and natural history from pancreatic neuroendocrine tumors”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] de Wilde, 2012, Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy, Nat. Rev. Gastroenterol. Hepatol. source

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    Premisecitation

    In a large multi-center international trial of high-risk cohorts, almost three-fourths of patients diagnosed with PDAC on active surveillance had Stage I disease, and an equal proportion were alive at five years.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Dbouk, 2022, The multicenter cancer of pancreas screening study: impact on stage and survival, J. Clin. Oncol. source

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    Premisecitation

    In the past decade, FOLFIRINOX and gemcitabine plus nab-paclitaxel became first-line therapies for advanced PDAC.

    “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.”
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    • cites [8] Conroy, 2011, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N. Engl. J. Med. source

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    • cites [9] Von Hoff, 2013, Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, N. Engl. J. Med. source

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    Premisecitation

    Current guidelines advise against screening the general population for PDAC and instead emphasize biomarker studies in well-defined high-risk cohorts.

    “current guidelines advise against screening the general population and instead emphasize biomarker studies be focused on well-defined high-risk cohorts44.”
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    • cites [44] Owens, 2019, Screening for pancreatic cancer: US Preventive Services Task Force reaffirmation recommendation statement, JAMA source

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    Premisecitation

    In retrospective analyses of a US national cancer surveillance database, about 80% of patients with Stage IA/IB PDAC were alive at five years, compared with less than 10% of those with advanced disease.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    • Rests on an assumption: Patients with Stage IA/IB PDAC are typically diagnosed incidentally and make up no more than 3–5% of cases.

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    Premisecitation

    Intraductal papillary mucinous neoplasms (IPMNs) are the most common cystic mucinous precursors, are macroscopic, and can be followed by imaging.

    “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.”
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    • cites [25] Matthaei, 2011, Cystic precursors to invasive pancreatic cancer, Nat. Rev. Gastroenterol. Hepatol. source

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    Pancreatic intraepithelial neoplasias (PanINs) are the most frequently observed precursor lesions and are microscopic, not visible on abdominal imaging.

    “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.”
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    • cites [24] Overbeek, 2016, Surveillance for neoplasia in the pancreas, Best Pract. Res. Clin. Gastroenterol. source

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    KRAS mutations are observed in most low-grade PanINs and IPMNs, suggesting KRAS is the initiating genetic event in exocrine neoplasia.

    “KRAS mutations are observed in most low-grade PanINs and IPMNs, suggesting KRAS is the initiating genetic event driving exocrine neoplasia46,47.”
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    • cites [46] Kanda, 2012, Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia, Gastroenterology source

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    • cites [47] Fujikura, 2021, Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions, Gut source

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    Deletion of KDM6A in GEMMs results in accelerated tumorigenesis and acquisition of an aggressive transcriptional subtype.

    “deletion of KDM6A results in accelerated tumorigenesis and acquisition of an aggressive transcriptional subtype95–97.”
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    • cites [95] Kalisz, 2020, HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer, EMBO J. source

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    • cites [96] Yi, 2022, KDM6A regulates cell plasticity and pancreatic cancer progression by noncanonical activin pathway, Cell. Mol. Gastroenterol. Hepatol. source

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    • cites [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

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    Altered p53 function has multiple tumor-promoting effects on neoplastic cells, including increased genomic instability, reprogrammed cellular metabolism, and enhanced metastatic propensity.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [30] Hingorani, 2005, Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice, Cancer Cell source

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    • cites [57] Morris, 2019, alpha-Ketoglutarate links p53 to cell fate during tumour suppression, Nature source

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    • cites [58] Rajeshkumar, 2015, Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function, Cancer Res. source

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    • cites [59] Weissmueller, 2014, Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling, Cell source

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    Premisecitation

    A pivotal clinical trial in PDAC patients with germline BRCA1/2 mutations established that an oral PARP inhibitor improved progression-free survival, leading to approval in this setting.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Golan, 2019, Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, N. Engl. J. Med. source

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    ATM mutations are the second most frequent known cause of germline mutations in PDAC after BRCA2 and confer a comparable lifetime increased risk of PDAC in carriers.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Hsu, 2021, Risk of pancreatic cancer among individuals with pathogenic variants in the ATM gene, JAMA Oncol. source

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    In the first published clinical series of KRASG12C inhibitor monotherapy in advanced PDAC, responses occurred in a minority (~21%) and were generally transient.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Strickler, 2023, Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer, N. Engl. J. Med. source

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    Interferon cluster loss creates a cold tumor immune milieu and resistance to immunotherapy.

    “Interferon cluster loss creates a “cold” tumor immune milieu and resistance to immunotherapy52”
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    • cites [52] Barriga, 2022, Machete identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis, Nat. Cancer source

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    • 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.

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    Premisecitation

    KRASG12C occurs in only 1.6% of PDAC cases, whereas KRASG12D is present in greater than 40%, followed by KRASG12V and KRASG12R.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Waters, 2018, KRAS: the critical driver and therapeutic target for pancreatic cancer, Cold Spring Harb. Perspect. Med. source

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    Chromatin remodeling and SWI/SNF complex genes are among the most frequently altered classes of genes in PDAC and can occur via somatic deletions of associated chromosomal loci.

    “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.”
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    • cites [45] 2017, Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma, Cancer Cell source

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    • cites [48] Jones, 2008, Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science source

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    • cites [49] Waddell, 2015, Whole genomes redefine the mutational landscape of pancreatic cancer, Nature source

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    • cites [50] Bailey, 2016, Genomic analyses identify molecular subtypes of pancreatic cancer, Nature source

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    • cites [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

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    Premisecitation

    Mauer et al. found that isolated epithelial tissues supported the Moffitt classical or basal-like subtypes, with no evidence of Bailey ADEX or Collisson exocrine-like subtypes in epithelial-enriched tumor samples.

    “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.”
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    • cites [132] Maurer, 2019, Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes, Gut source

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    These three subtypes could predict drug response in cell culture models, and patient outcomes differed significantly across subtypes.

    “these subtypes could predict drug response in cell culture models, and patient outcomes were significantly different across their subtypes.”
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    • cites [130] Collisson, 2011, Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy, Nat. Med. source

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    Deletion of Sox9 prevented KRAS-driven transformation, while Sox9 overexpression accelerated PanIN development.

    “Deletion of the ductal progenitor gene Sox9 prevented KRAS-driven transformation, while Sox9 overexpression accelerated PanIN development.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Kopp, 2012, Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma, Cancer Cell source

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    Samples with ADEX or exocrine-like signatures are associated with low PDAC cellularity, suggesting these signals derive from stromal, immune, or non-cancerous elements.

    “samples “ADEX” or “exocrine-like” signatures are associated with low PDAC cellularity45, suggesting these signals derive from stromal/immune/non-cancerous elements of tissues.”
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    • cites [45] 2017, Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma, Cancer Cell source

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    Moffitt and colleagues used a virtual dissection strategy to computationally subtract stromal and immune transcriptional background from bulk RNA sequencing and identified classical and basal-like tumor subtypes plus normal and activated stromal subtypes.

    “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”.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Moffitt, 2015, Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma, Nat. Genet. source

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    Premisecitation

    Puleo et al. suggested that the Bailey ADEX subtype is likely contamination from pancreatic acinar cells.

    “they suggested that their findings demonstrate that the Bailey ADEX subtype is likely contamination of pancreatic acinar cells.”
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    • cites [133] Puleo, 2018, Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features, Gastroenterology source

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    Consensus on PDAC transcriptional subtypes has converged on two main groups, classical and basal-like, with some tumors showing mixed features.

    “consensus has best coalesced around two major subtypes, classical and basal-like, with some populations showing mixed features135”
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    • cites [135] Collisson, 2019, Molecular subtypes of pancreatic cancer, Nat. Rev. Gastroenterol. Hepatol. source

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    Fibroblasts are the most abundant cell type in the PDAC tumor microenvironment and are largely responsible for extracellular matrix deposition that drives characteristic physiological properties of PDAC.

    “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”
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    • cites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source

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    TP63 can promote more aggressive PDAC subtypes and can be induced by KDM6A loss.

    “several candidate regulators such as TP63136, which can be induced by KDM6A loss97, can promote more aggressive subtypes”
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    • cites [136] Somerville, 2018, TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma, Cell Rep. source

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    • cites [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

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    Premisecitation

    Chan-Seng-Yu and colleagues identified five PDAC subtypes-basal-like-A, basal-like-B, hybrid, classical-A, and classical-B-using LCM enrichment of epithelial tissue from advanced PDAC patients with whole-genome and transcriptomic sequencing.

    “They identified five different subtypes of PDAC tumors: “basal-like-A”, “basal-like-B”, “hybrid”, “classical-A” and “classical-B”.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Chan-Seng-Yue, 2020, Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution, Nat. Genet. source

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    Chan-Seng-Yu et al. reported best overlap with Moffitt subtypes, and their hybrid subtype did not consistently fall into previously reported classes.

    “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.”
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    • cites [134] Chan-Seng-Yue, 2020, Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution, Nat. Genet. source

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    apCAF transcriptional profiles overlap with mesothelial cells and are postulated to derive from a mesothelial origin.

    “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”
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    • cites [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

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    • cites [145] Han, 2023, The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis, Nat. Commun. source

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    Premisecitation

    CD40 agonists reprogram macrophages to a less immunosuppressive status, leading to CD8 T cell infiltration and conversion from a cold to a hot tumor.

    “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”
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    • cites [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

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    Premisecitation

    Targeting MDSCs and/or TAMs improves adaptive immune responses in mouse models of pancreatic cancer and can potentiate checkpoint inhibition.

    “targeting MDSCs and/or TAMs improves adaptive immune responses in mouse models of pancreatic cancer and can potentiate checkpoint inhibition approaches176,177,179,180”
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    • cites [176] Pylayeva-Gupta, 2012, Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia, Cancer Cell source

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    • cites [177] Zhu, 2017, Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression, Immunity source

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    • cites [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

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    Depletion of FAP+ fibroblasts or targeting CXCL12 sensitizes PDAC to immune checkpoint blockade in preclinical models.

    “Depletion of these fibroblasts, or targeting of CXCL12, sensitizes PDAC to immune checkpoint blockade in preclinical models151”
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    • cites [151] Hutton, 2021, Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity, Cancer Cell source

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    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.

    “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”
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    PDAC cells produce low tonic levels of a distinct oncogenic homo-trimeric collagen that binds α3β1 integrin, mediating immune suppression and reprogramming the tumor-associated microbiome.

    “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”
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    • cites [167] Aguilera, 2017, Inhibition of discoidin domain Receptor 1 reduces collagen-mediated tumorigenicity in pancreatic ductal adenocarcinoma, Mol. Cancer Ther. source

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    FAK is hyperactivated in pancreatic cancer cells and is an important driver of fibrosis and immune suppression in the TME.

    “Focal adhesion kinase (FAK), hyperactivated in pancreatic cancer cells, is an important driver of fibrosis and immune suppression in the TME174”
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    • cites [174] Lander, 2022, Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade, Cancer Discov. source

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  • May combine two claims.

    Premisecitation

    FAK inhibition markedly reduced fibrosis and decreased infiltration of tumor-promoting immune cells in mice.

    “FAK inhibition was shown to markedly reduced fibrosis and decreased the infiltration of tumor-promoting immune cells in mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FAP-expressing CAFs also express high levels of CXCL12 and inhibit tumor T cell infiltration.

    “CAFs expressing Fibroblast Activation Protein (FAP) also express high levels of CXCL12 and inhibit tumor T cell infiltration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Hutton, 2021, Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dendritic cells are found in low numbers in PDAC compared with other tumor types, and the DCs present are of poor quality for antigen presentation.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] Byrne, 2016, CD40 stimulation obviates innate sensors and drives T cell immunity in cancer, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The majority of collagen in PDAC is type I collagen, largely generated by CAFs.

    “The majority of collagen is type I collagen164, largely generated by CAFs147,165”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [164] Hosein, 2020, Pancreatic cancer stroma: an update on therapeutic targeting strategies, Nat. Rev. Gastroenterol. Hepatol. source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [165] Chen, 2021, Type I collagen deletion in alphaSMA(+) myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oncogenic KRAS signaling drives GM-CSF expression by PDAC cells, promoting recruitment of immunosuppressive MDSCs.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [176] Pylayeva-Gupta, 2012, Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia, Cancer Cell source

      Not checked in the free run.

    • cites [177] Zhu, 2017, Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression, Immunity source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyaluronic acid is a glycosaminoglycan polymer released predominantly by CAFs that retains water and promotes the high interstitial fluid pressure characteristic of pancreatic tumors.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeted deletion of type I collagen from SMA-expressing fibroblasts increases immune suppressive myeloid infiltration and accelerates tumor progression.

    “Targeted deletion of type I collagen from SMA-expressing fibroblasts increases immune suppressive myeloid infiltration, accelerating tumor progression166”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MyCAFs localize near neoplastic cells and are thought to deposit extracellular matrix, whereas iCAFs occupy spaces between PDAC cell islands and release IL6 and other anti-inflammatory cytokines.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MyCAF and iCAF populations have been identified among CAFs.

    “Early efforts to identify and understand different CAF populations identified a myofibroblast-like population (myCAF) and an inflammatory fibroblast population (iCAF)147”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    CAFs are largely responsible for deposition of the dense extracellular matrix in PDAC, which consists largely of collagen and hyaluronic acid.

    “CAFs are largely responsible for deposition of the dense extracellular matrix found in PDAC, largely consisting of collagen and hyaluronic acid.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD11b/CD18 agonists developed in PDAC models have shown promising preclinical data and are being tested in the clinic.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [181] DeNardo, 2021, GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors, J. Immunother. Cancer source

      Not checked in the free run.

    • cites [182] Vonderheide, 2020, CD40 agonist antibodies in cancer immunotherapy, Annu. Rev. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    LRRC15+ fibroblasts are present in mouse PDAC but not normal pancreas and are postulated to promote tumor growth and inhibit anti-tumor immune responses.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FAK inhibition-mediated stromal reprogramming overcomes radiation resistance and sensitizes tumors to immunotherapy.

    “FAK inhibition-mediated reprogramming of the stroma was shown to overcome radiation resistance and sensitize the tumors to immunotherapy175”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Bayne, 2012, Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The non-oxidative pentose phosphate pathway enables nucleotide biosynthesis, and the hexosamine biosynthesis pathway generates GlcNAc for posttranslational modifications.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Ying, 2012, Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source

      Not checked in the free run.

    • cites [195] Boudreau, 2016, Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition, Nat. Chem. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Combined pharmacological targeting of MEK or ERK with hydroxychloroquine potently inhibits xenograft tumor growth and has shown efficacy in clinical treatment of PDAC.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pancreatic cancer cells exhibit increased lysosome biogenesis and constitutive engagement of autophagy.

    “increased biogenesis of lysosomes and constitutive engagement of the autophagy “self-eating” recycling program206”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [206] Yang, 2011, Pancreatic cancers require autophagy for tumor growth, Genes Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased NCOA4 accelerates tumorigenesis in mice, and genetic ablation delays tumor growth that is eventually overcome by compensatory iron acquisition pathways.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [216] Ravichandran, 2022, Coordinated transcriptional and catabolic programs support iron-dependent adaptation to RAS-MAPK pathway inhibition in pancreatic cancer, Cancer Discov. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oncogenic Ras drives glutamine anaplerosis to supply carbon for the TCA cycle, glutathione biosynthesis for ROS detoxification, and a non-canonical malate-aspartate shuttle for NADPH production.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Biancur, 2017, Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism, Nat. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DON was identified as a potential anti-cancer glutamine antagonist more than half a century ago, but its lack of substrate specificity caused too much off-target toxicity.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent advances have optimized DON as a pro-drug with pharmacokinetic properties that increase tumor targeting, including an orally available analog with promising preclinical results in murine PDAC models.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [203] Leone, 2019, Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion, Science source

      Not checked in the free run.

    • cites [204] Sharma, 2020, Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy, J. Clin. Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MEK inhibition in PDAC increases lysosome biosynthesis and ferritinophagy, which are necessary to support increased iron-sulfur cluster proteins for respiration.

    “MEK-inhibition in PDAC increased both lysosome biosynthesis and ferritinophagy, necessary to support increased iron-sulfur cluster proteins for respiration217”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Dixon, 2012, Ferroptosis: an iron-dependent form of nonapoptotic cell death, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MHC-I expression is low at the PDAC cell surface and is predominantly localized within autophagosomes and lysosomes.

    “MHC-I expression is low at the PDAC cell surface, instead found predominantly localized within autophagosomes and lysosomes227”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [227] Zhu, 2021, Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells, Cell Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Labile iron can potentiate cell death via ferroptosis.

    “Labile iron can also potentiate cell death via the lipid oxidation process known as “ferroptosis”218”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Badgley, 2020, Cysteine depletion induces pancreatic tumor ferroptosis in mice, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ferritin is trafficked to autophagosomes via NCOA4, and free iron is subsequently released by autophagy through ferritinophagy.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Pantopoulos, 2012, Mechanisms of mammalian iron homeostasis, Biochemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutant KRAS drives upregulated glycolysis, increasing lactate production and providing carbon inputs for synthesis of molecules required for proliferation.

    “Mutant KRAS drives upregulated glycolysis, not only increasing production of lactate, but also providing key carbon inputs for synthesis of molecules required for proliferation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Ying, 2012, Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source

      Not checked in the free run.

    • cites [195] Boudreau, 2016, Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition, Nat. Chem. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The shift in immune infiltration after Treg depletion follows loss of myCAFs, as Tregs are a significant source of TGF-beta.

    “This shift in immune infiltration follows a loss of myCAFs upon Treg depletion, as Tregs proved a significant source of TGF-beta.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Kamphorst, 2015, Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein, Cancer Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Differential activation of the integrated stress response can define subpopulations within individual tumors and drives differential sensitivity to metabolic inhibitors.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [239] Recouvreux, 2020, Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer, J. Exp. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High glycolytic flux is required to maintain upregulated PGD metabolism, and this is maintained in part through suppression of TXNIP transcription.

    “High glycolytic flux is required to maintain upregulated PGD metabolism, and this in maintained in part through suppression of thioredoxin-interacting protein (TXNIP) transcription243.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [243] Sancho, 2015, MYC/PGC-1alpha balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only a subset of PDAC cell lines with mutant KRAS demonstrate a constitutive macropinocytosis program, while others engage this process only when challenged with glutamine deprivation.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The metabolic milieu in pancreatic tumors is deregulated, with some nutrients enriched and others depleted.

    “the metabolic milieu in pancreatic tumors is deregulated, with some nutrients being enriched and others depleted.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The glycolytic metabolic subtype aligns with a quasimesenchymal transcriptional subtype, and the lipogenic metabolic state aligns with a classical signature.

    “The glycolytic metabolic subtype aligns with a “quasimesenchymal” transcriptional subtype and lipogenic metabolism state with a “classical” signature130.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Collisson, 2011, Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deoxycytidine released among these pyrimidines inhibits gemcitabine efficacy, and depletion of myeloid cells in mice sensitizes PDAC tumors to gemcitabine treatment.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [258] Dalin, 2019, Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance, Cancer Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These metabolic adaptations enable PDAC cells to survive nutrient-challenging conditions in the primary tumor and provide metabolic flexibility for metastasis.

    “These combine to enable PDAC cells to survive nutrient challenging conditions in the primary tumor and provide metabolic flexibility to enable metastasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Metabolic inhibition approaches combined with RAS pathway inhibitors have shown strong preclinical data and are currently in clinical trials.

    “metabolic inhibition approaches combined with RAS pathway inhibitors have shown strong pre-clinical data and are currently in clinical trials197,224,225”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [197] Son, 2013, Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway, Nature source

      Not checked in the free run.

    • cites [224] Kinsey, 2019, Protective autophagy elicited by RAF-->MEK-->ERK inhibition suggests a treatment strategy for RAS-driven cancers, Nat. Med. source

      Not checked in the free run.

    • cites [225] Garrido, 2016, The urgent need to recover MHC class I in cancers for effective immunotherapy, Curr. Opin. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During passaging, patient-derived organoids change their transcriptional profiles and subpopulation proportions.

    “Further, patient-derived organoid transcriptional landscape and sub-population proportions shift during passaging137,271”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [137] Raghavan, 2021, Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer, Cell source

      Not checked in the free run.

    • cites [271] Schalck, 2022, Single-cell sequencing reveals trajectory of tumor-infiltrating lymphocyte states in pancreatic cancer, Cancer Discov. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adding contextual factors absent from ex vivo cultures may restore original tumor heterogeneity and preserve the capacity to predict therapy response.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Raghavan, 2021, Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Single-cell RNA sequencing confirmed that human and murine pancreatic tumors contain multiple CAF populations and enabled apCAF discovery.

    “scRNA-seq data confirmed the existence of multiple CAF populations within human and murine pancreatic tumors and allowed the discovery of apCAFs149.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Increased understanding of nutrient symbiotic support mechanisms in the pancreatic TME has identified several therapeutic opportunities.

    “However, our increased understanding of the symbiotic support mechanisms of nutrients within the pancreatic TME have already identified several therapeutic opportunities.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neural invasion is a well-recognized feature of pancreatic tumors, and its severity negatively correlates with prognosis.

    “Neural invasion is a well-recognized feature of pancreatic tumors, with the severity negatively correlating to prognosis262.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [262] Banh, 2020, Neurons release serine to support mRNA translation in pancreatic cancer, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Greater knowledge of PDAC biology has produced numerous treatment trials, yet most have not met expectations.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Among common solid cancers, PDAC is among the most frequent to fail Phase 3 trials.

  • May combine two claims.

    Premisecitation

    The same analyses found signs of systemic CD8 T cell exhaustion, and network analysis pointed to TIGIT as a central immune-suppression node.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [277] Freed-Pastor, 2021, The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combining several scRNA-seq datasets with lineage tracing showed that ap-CAFs may originate from mesothelium and drive regulatory T cell expansion and immune suppression.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Han, 2023, The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis, Nat. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Such combinations may both shrink tumors and release antigens in situ to enable an immune response.

    “This has the dual benefit of tumor shrinkage and acts as an in situ antigen release mechanism to allow for an immune response.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    There have been calls to reform PDAC drug development and to revise the criteria for advancing agents into larger trials.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

    • Rests on an assumption: Among common solid cancers, PDAC is among the most frequent to fail Phase 3 trials.

  • May combine two claims.

    Premisecitation

    Combining spatial profiling and single-nucleus RNA sequencing allowed study of PDAC response to neoadjuvant therapy and revealed a treatment-refractory neural-like progenitor population that evades standard regimens.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [279] He, 2022, High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging, Nat. Biotechnol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although immune infiltration and behavior varied among patients, spatial analysis revealed extensive heterogeneity within individual patients.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [275] Kiemen, 2022, CODA: quantitative 3D reconstruction of large tissues at cellular resolution, Nat. Methods source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Targeting metabolism in PDAC is not simply a matter of defining metabolic vulnerabilities of cancer cells; PDAC cell metabolic state is heterogeneous within individual tumors.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A recent preclinical study found that a 41-BB agonist plus LAG-3 inhibitor targeting CD8 T cell checkpoints failed alone, but adding a myeloid-targeted CXCR1/2 antagonist produced durable responses in biologically relevant models.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sonic hedgehog inhibition to inactivate CAFs failed in patients, and later preclinical studies identified explanations for that failure.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [289] Özdemir, 2015, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Cancer Cell source

      Not checked in the free run.

    • cites [159] Özdemir, 2014, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Cancer Cell source

      Not checked in the free run.

    • cites [290] Hingorani, 2023, Epithelial and stromal co-evolution and complicity in pancreatic cancer, Nat. Rev. Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Preclinical work proposed that systemic therapy would work better if it could penetrate the dense fibrosis and high interstitial pressure generated by CAFs in pancreatic tumors.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [140] Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell source

      Not checked in the free run.

    • cites [158] Rhim, 2014, Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Although pancreatic cancer biology has advanced considerably over recent decades, this has not produced a major clinical breakthrough for most patients.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Among common solid cancers, PDAC is among the most frequent to fail Phase 3 trials.

  • May combine two claims.

    Interpretationreasoning

    Although preclinical models are imperfect, they can reveal possible reasons for failure when clinical trials do not succeed.

    “While preclinical models remain far from perfect, they do offer valuable insights into potential mechanisms of failure when trials are unsuccessful.”
    Quote in the paperNot a substantial claim
87 of 87

  • 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.”
14 of 14

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Each contradiction between two passages listed here was confirmed by an independent check.

  • GM-CSF is given two different names

    Minor

    The text expands GM-CSF as granulocyte colony stimulating factor, while a cited reference expands it as granulocyte-macrophage colony-stimulating factor. Those names denote different factors.

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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)
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2023-04
Volume
186
Issue
8
Pages
1729-1754
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2023.02.014
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
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 › Surgery › 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

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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