Pancreatic cancer: Advances and challenges

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.”

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

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”

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

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”

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

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.”

What the sources say

• Not checked yetcites [8] Conroy, 2011, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N. Engl. J. Med. source
• Not checked yetcites [9] Von Hoff, 2013, Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, N. Engl. J. Med. source

In the paper

“current guidelines advise against screening the general population and instead emphasize biomarker studies be focused on well-defined high-risk cohorts44.”

What the sources say

• Not checked yetcites [44] Owens, 2019, Screening for pancreatic cancer: US Preventive Services Task Force reaffirmation recommendation statement, JAMA source

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.”

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

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.”

What the sources say

• Not checked yetcites [25] Matthaei, 2011, Cystic precursors to invasive pancreatic cancer, Nat. Rev. Gastroenterol. Hepatol. source

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.”

What the sources say

• Not checked yetcites [24] Overbeek, 2016, Surveillance for neoplasia in the pancreas, Best Pract. Res. Clin. Gastroenterol. source

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.”

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

In the paper

“deletion of KDM6A results in accelerated tumorigenesis and acquisition of an aggressive transcriptional subtype95–97.”

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

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.”

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

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.”

What the sources say

• Not checked yetcites [87] Golan, 2019, Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, N. Engl. J. Med. source

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.”

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

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.”

What the sources say

• Not checked yetcites [75] Strickler, 2023, Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer, N. Engl. J. Med. source

In the paper

“Interferon cluster loss creates a “cold” tumor immune milieu and resistance to immunotherapy52”

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

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.”

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

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.”

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

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.”

What the sources say

• Not checked yetcites [132] Maurer, 2019, Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes, Gut source

In the paper

“these subtypes could predict drug response in cell culture models, and patient outcomes were significantly different across their subtypes.”

What the sources say

• Not checked yetcites [130] Collisson, 2011, Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy, Nat. Med. source

In the paper

“Deletion of the ductal progenitor gene Sox9 prevented KRAS-driven transformation, while Sox9 overexpression accelerated PanIN development.”

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

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.”

What the sources say

• Not checked yetcites [45] 2017, Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma, Cancer Cell source

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”.”

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

In the paper

“they suggested that their findings demonstrate that the Bailey ADEX subtype is likely contamination of pancreatic acinar cells.”

What the sources say

• Not checked yetcites [133] Puleo, 2018, Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features, Gastroenterology source

In the paper

“consensus has best coalesced around two major subtypes, classical and basal-like, with some populations showing mixed features135”

What the sources say

• Not checked yetcites [135] Collisson, 2019, Molecular subtypes of pancreatic cancer, Nat. Rev. Gastroenterol. Hepatol. source

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”

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

In the paper

“several candidate regulators such as TP63136, which can be induced by KDM6A loss97, can promote more aggressive subtypes”

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

In the paper

“They identified five different subtypes of PDAC tumors: “basal-like-A”, “basal-like-B”, “hybrid”, “classical-A” and “classical-B”.”

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

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.”

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

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”

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

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”

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

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”

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

In the paper

“Depletion of these fibroblasts, or targeting of CXCL12, sensitizes PDAC to immune checkpoint blockade in preclinical models151”

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

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”

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”

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

In the paper

“Focal adhesion kinase (FAK), hyperactivated in pancreatic cancer cells, is an important driver of fibrosis and immune suppression in the TME174”

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

In the paper

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

In the paper

“CAFs expressing Fibroblast Activation Protein (FAP) also express high levels of CXCL12 and inhibit tumor T cell infiltration.”

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

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”

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

In the paper

“The majority of collagen is type I collagen164, largely generated by CAFs147,165”

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

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”

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

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”

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

In the paper

“Targeted deletion of type I collagen from SMA-expressing fibroblasts increases immune suppressive myeloid infiltration, accelerating tumor progression166”

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

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.”

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

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”

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

In the paper

“CAFs are largely responsible for deposition of the dense extracellular matrix found in PDAC, largely consisting of collagen and hyaluronic acid.”

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

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”

What the sources say

• Not checked yetcites [181] DeNardo, 2021, GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors, J. Immunother. Cancer source
• Not checked yetcites [182] Vonderheide, 2020, CD40 agonist antibodies in cancer immunotherapy, Annu. Rev. Med. source

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”

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

In the paper

“FAK inhibition-mediated reprogramming of the stroma was shown to overcome radiation resistance and sensitize the tumors to immunotherapy175”

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

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”

What the sources say

• Not checked yetcites [64] Ying, 2012, Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source
• Not checked yetcites [195] Boudreau, 2016, Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition, Nat. Chem. Biol. source

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.”

In the paper

“increased biogenesis of lysosomes and constitutive engagement of the autophagy “self-eating” recycling program206”

What the sources say

• Not checked yetcites [206] Yang, 2011, Pancreatic cancers require autophagy for tumor growth, Genes Dev. source

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”

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

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”

What the sources say

• Not checked yetcites [198] Biancur, 2017, Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism, Nat. Commun. source

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.”

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

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”

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

In the paper

“MEK-inhibition in PDAC increased both lysosome biosynthesis and ferritinophagy, necessary to support increased iron-sulfur cluster proteins for respiration217”

What the sources say

• Not checked yetcites [217] Dixon, 2012, Ferroptosis: an iron-dependent form of nonapoptotic cell death, Cell source

In the paper

“MHC-I expression is low at the PDAC cell surface, instead found predominantly localized within autophagosomes and lysosomes227”

What the sources say

• Not checked yetcites [227] Zhu, 2021, Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells, Cell Metab. source

In the paper

“Labile iron can also potentiate cell death via the lipid oxidation process known as “ferroptosis”218”

What the sources say

• Not checked yetcites [218] Badgley, 2020, Cysteine depletion induces pancreatic tumor ferroptosis in mice, Science source

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”

What the sources say

• Not checked yetcites [214] Pantopoulos, 2012, Mechanisms of mammalian iron homeostasis, Biochemistry source

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.”

What the sources say

• Not checked yetcites [64] Ying, 2012, Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source
• Not checked yetcites [195] Boudreau, 2016, Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition, Nat. Chem. Biol. source

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.”

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

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.”

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

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.”

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

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”

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

In the paper

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

In the paper

“The glycolytic metabolic subtype aligns with a “quasimesenchymal” transcriptional subtype and lipogenic metabolism state with a “classical” signature130.”

What the sources say

• Not checked yetcites [130] Collisson, 2011, Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy, Nat. Med. source

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.”

What the sources say

• Not checked yetcites [258] Dalin, 2019, Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance, Cancer Res. source

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.”

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”

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

In the paper

“Further, patient-derived organoid transcriptional landscape and sub-population proportions shift during passaging137,271”

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

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.”

What the sources say

• Not checked yetcites [137] Raghavan, 2021, Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer, Cell source

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.”

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

In the paper

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

In the paper

“Neural invasion is a well-recognized feature of pancreatic tumors, with the severity negatively correlating to prognosis262.”

What the sources say

• Not checked yetcites [262] Banh, 2020, Neurons release serine to support mRNA translation in pancreatic cancer, Cell source

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.”

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.”

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

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.”

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

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.”

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.”

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

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.”

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

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.”

What the sources say

• Not checked yetcites [275] Kiemen, 2022, CODA: quantitative 3D reconstruction of large tissues at cellular resolution, Nat. Methods source

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.”

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.”

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

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.”

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

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.”

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

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.”

In the paper

“While preclinical models remain far from perfect, they do offer valuable insights into potential mechanisms of failure when trials are unsuccessful.”