1932

Abstract

Pancreatic cancer is a notoriously deadly disease characterized by many challenges in clinical management. Despite important advances in our understanding of pancreatic cancer progression and its underlying molecular biology over the last decades, there is a long road ahead if we aim to meaningfully improve patient outcomes in this difficult disease. Treatment options remain limited, and patient prognosis, although improving, remains bleak. As we build toward the future, we propose a framework for targeting the seven deadly hallmarks of pancreatic cancer in an effort to cure this disease. The high mortality and aggressive nature of pancreatic cancer can be largely ascribed to () diagnostic deficiencies, () chronic inflammation, () desmoplastic stroma, () early metastasis, () KRAS signaling, () metabolism, and () rapid deconditioning. Here, we outline the challenges presented by each of these disease hallmarks and highlight ongoing research to tackle each one.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-060624-044323
2025-04-11
2025-04-18
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/9/1/annurev-cancerbio-060624-044323.html?itemId=/content/journals/10.1146/annurev-cancerbio-060624-044323&mimeType=html&fmt=ahah

Literature Cited

  1. Adams CR, Htwe HH, Marsh T, Wang AL, Montoya ML, et al. 2019.. Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer. . eLife 8::e45313
    [Crossref] [Google Scholar]
  2. Aiello NM, Maddipati R, Norgard RJ, Balli D, Li J, et al. 2018.. EMT subtype influences epithelial plasticity and mode of cell migration. . Dev. Cell 45:(6):68195.e4
    [Crossref] [Google Scholar]
  3. Alonso-Curbelo D, Ho Y-J, Burdziak C, Maag JLV, Morris JP, et al. 2021.. A gene-environment-induced epigenetic program initiates tumorigenesis. . Nature 590:(7847):64248
    [Crossref] [Google Scholar]
  4. Andricovich J, Perkail S, Kai Y, Casasanta N, Peng W, Tzatsos A. 2018.. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors. . Cancer Cell 33:(3):51226.e8
    [Crossref] [Google Scholar]
  5. Asahina K, Balog S, Hwang E, Moon E, Wan E, et al. 2020.. Moderate alcohol intake promotes pancreatic ductal adenocarcinoma development in mice expressing oncogenic Kras. . Am. J. Physiol. Gastrointest. Liver Physiol. 318:(2):G26576
    [Crossref] [Google Scholar]
  6. Auciello FR, Bulusu V, Oon C, Tait-Mulder J, Berry M, et al. 2019.. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. . Cancer Discov. 9:(5):61727
    [Crossref] [Google Scholar]
  7. Babic A, Rosenthal MH, Bamlet WR, Takahashi N, Sugimoto M, et al. 2019.. Postdiagnosis loss of skeletal muscle, but not adipose tissue, is associated with shorter survival of patients with advanced pancreatic cancer. . Cancer Epidemiol. Biomarkers Prev. 28:(12):206269
    [Crossref] [Google Scholar]
  8. Babic A, Rosenthal MH, Sundaresan TK, Khalaf N, Lee V, et al. 2023.. Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer. . Nat. Commun. 14:(1):4317
    [Crossref] [Google Scholar]
  9. Bachmann J, Heiligensetzer M, Krakowski-Roosen H, Büchler MW, Friess H, Martignoni ME. 2008.. Cachexia worsens prognosis in patients with resectable pancreatic cancer. . J. Gastrointest. Surg. 12:(7):1193201
    [Crossref] [Google Scholar]
  10. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, et al. 2016.. Genomic analyses identify molecular subtypes of pancreatic cancer. . Nature 531:(7592):4752
    [Crossref] [Google Scholar]
  11. Batlle E, Clevers H. 2017.. Cancer stem cells revisited. . Nat. Med. 23:(10):112434
    [Crossref] [Google Scholar]
  12. Bear AS, Vonderheide RH, O'Hara MH. 2020.. Challenges and opportunities for pancreatic cancer immunotherapy. . Cancer Cell 38:(6):788802
    [Crossref] [Google Scholar]
  13. Bechard ME, Smalling R, Hayashi A, Zhong Y, Word AE, et al. 2020.. Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis. . Nat. Commun. 11:(1):4055
    [Crossref] [Google Scholar]
  14. Biancur DE, Kapner KS, Yamamoto K, Banh RS, Neggers JE, et al. 2021.. Functional genomics identifies metabolic vulnerabilities in pancreatic cancer. . Cell Metab. 33:(1):199210.e8
    [Crossref] [Google Scholar]
  15. Biancur DE, Paulo JA, Małachowska B, Quiles Del Rey M, Sousa CM, et al. 2017.. Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. . Nat. Commun. 8:(1):15965
    [Crossref] [Google Scholar]
  16. Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, et al. 2019.. Il1-induced Jak/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. . Cancer Discov. 9:(2):282301
    [Crossref] [Google Scholar]
  17. Boj SF, Hwang C-I, Baker LA, Chio IIC, Engle DD, et al. 2015.. Organoid models of human and mouse ductal pancreatic cancer. . Cell 160:(1–2):32438
    [Crossref] [Google Scholar]
  18. Brand RE, Persson J, Bratlie SO, Chung DC, Katona BW, et al. 2022.. Detection of early-stage pancreatic ductal adenocarcinoma from blood samples: results of a multiplex biomarker signature validation study. . Clin. Transl. Gastroenterol. 13:(3):E00468
    [Crossref] [Google Scholar]
  19. Brunton H, Caligiuri G, Cunningham R, Upstill-Goddard R, Bailey UM, et al. 2020.. HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer. . Cell Rep. 31:(6):107625
    [Crossref] [Google Scholar]
  20. Burdziak C, Alonso-Curbelo D, Walle T, Reyes J, Barriga FM, et al. 2023.. Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis. . Science 380:(6645):eadd5327
    [Crossref] [Google Scholar]
  21. Caligiuri G, Tuveson DA. 2023.. Activated fibroblasts in cancer: perspectives and challenges. . Cancer Cell 41:(3):43449
    [Crossref] [Google Scholar]
  22. Cao K, Xia Y, Yao J, Han X, Lambert L, et al. 2023.. Large-scale pancreatic cancer detection via non-contrast CT and deep learning. . Nat. Med. 29:(12):303343
    [Crossref] [Google Scholar]
  23. Carpenter ES, Elhossiny AM, Kadiyala P, Li J, McGue J, et al. 2023.. Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic lesions. . Cancer Discov. 13:(6):132445
    [Crossref] [Google Scholar]
  24. Carrer A, Trefely S, Zhao S, Campbell SL, Norgard RJ, et al. 2019.. Acetyl-CoA metabolism supports multi-step pancreatic tumorigenesis. . Cancer Discov. 9:(3):41635
    [Crossref] [Google Scholar]
  25. Chan-Seng-Yue M, Kim JC, Wilson GW, Ng K, Figueroa EF, et al. 2020.. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. . Nat. Genet. 52:(2):23140
    [Crossref] [Google Scholar]
  26. Cheng DK, Oni TE, Thalappillil JS, Park Y, Ting HC, et al. 2021.. Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer. . PNAS 118:(21):e2016904118
    [Crossref] [Google Scholar]
  27. Chitty JL, Yam M, Perryman L, Parker AL, Skhinas JN, et al. 2023.. A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer. . Nat. Cancer 4:(9):132644
    [Crossref] [Google Scholar]
  28. Chung KM, Singh J, Lawres L, Dorans KJ, Garcia C, et al. 2020.. Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma. . Cell 181:(4):83247.e18
    [Crossref] [Google Scholar]
  29. Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, et al. 2018.. Detection and localization of surgically resectable cancers with a multi-analyte blood test. . Science 359:(6378):92630
    [Crossref] [Google Scholar]
  30. Collins MA, Bednar F, Zhang Y, Brisset JC, Galbán S, et al. 2012a.. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. . J. Clin. Investig. 122:(2):63953
    [Crossref] [Google Scholar]
  31. Collins MA, Brisset JC, Zhang Y, Bednar F, Pierre J, et al. 2012b.. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. . PLOS ONE 7:(12):e49707
    [Crossref] [Google Scholar]
  32. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, et al. 2011.. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. . Nat. Med. 17:(4):5003
    [Crossref] [Google Scholar]
  33. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, et al. 2013.. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. . Nature 497:(7451):63337
    [Crossref] [Google Scholar]
  34. Daemen A, Peterson D, Sahu N, McCord R, Du X, et al. 2015.. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. . PNAS 112:(32):E441017
    [Crossref] [Google Scholar]
  35. Dalin S, Sullivan MR, Lau AN, Grauman-Boss B, Mueller HS, et al. 2019.. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. . Cancer Res. 79:(22):572333
    [Crossref] [Google Scholar]
  36. Daniluk J, Liu Y, Deng D, Chu J, Huang H, et al. 2012.. An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. . J. Clin. Investig. 122:(4):151928
    [Crossref] [Google Scholar]
  37. Dbouk M, Katona BW, Brand RE, Chak A, Syngal S, et al. 2022.. The multicenter cancer of pancreas screening study: impact on stage and survival. . J. Clin. Oncol. 40:(28):325766
    [Crossref] [Google Scholar]
  38. Decker-Farrell AR, Ma A, Li F, Muir A, Olive KP. 2023.. Generation and ex vivo culture of murine and human pancreatic ductal adenocarcinoma tissue slice explants. . STAR Protoc. 4:(4):102711
    [Crossref] [Google Scholar]
  39. Del Poggetto E, Ho IL, Balestrieri C, Yen EY, Zhang S, et al. 2021.. Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis. . Science 373:(6561):eabj0486
    [Crossref] [Google Scholar]
  40. Demyan L, Habowski AN, Plenker D, King DA, Standring OJ, et al. 2022.. Pancreatic cancer patient-derived organoids can predict response to neoadjuvant chemotherapy. . Ann. Surg. 276:(3):45062
    [Crossref] [Google Scholar]
  41. DeNardo DG, Ruffell B. 2019.. Macrophages as regulators of tumor immunity and immunotherapy. . Nat. Rev. Immunol. 19:(6):36982
    [Crossref] [Google Scholar]
  42. Denicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, et al. 2011.. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. . Nature 475:(7354):1069
    [Crossref] [Google Scholar]
  43. Dey P, Kimmelman AC, Depinho RA. 2021.. Metabolic codependencies in the tumor microenvironment. . Cancer Discov. 11:(5):106781
    [Crossref] [Google Scholar]
  44. Di Chiaro P, Nacci L, Arco F, Brandini S, Polletti S, et al. 2024.. Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer. . Cancer Cell 42:(4):66281.e10
    [Crossref] [Google Scholar]
  45. Dongre A, Weinberg RA. 2018.. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. . Nat. Rev. Mol. Cell Biol. 20:(2):6984
    [Crossref] [Google Scholar]
  46. Du W, Phinney NZ, Huang H, Wang Z, Westcott J, et al. 2021.. AXL is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. . Mol. Cancer Res. 19:(8):141221
    [Crossref] [Google Scholar]
  47. Eibl G, Rozengurt E. 2021.. Obesity and pancreatic cancer: insight into mechanisms. . Cancers 13:(20):5067
    [Crossref] [Google Scholar]
  48. Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, et al. 2019.. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. . Cancer Discov. 9:(8):110223
    [Crossref] [Google Scholar]
  49. Encarnación-Rosado J, Kimmelman AC. 2021.. Harnessing metabolic dependencies in pancreatic cancers. . Nat. Rev. Gastroenterol. Hepatol. 18:(7):48292
    [Crossref] [Google Scholar]
  50. England CG, Hernandez R, Eddine SBZ, Cai W. 2016.. Molecular imaging of pancreatic cancer with antibodies. . Mol. Pharm. 13:(1):824
    [Crossref] [Google Scholar]
  51. Engle DD, Tiriac H, Rivera KD, Pommier A, Whalen S, et al. 2019.. The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. . Science 364:(6446):115662
    [Crossref] [Google Scholar]
  52. Feig C, Jones JO, Kraman M, Wells RJB, Deonarine A, et al. 2013.. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. . PNAS 110:(50):2021217
    [Crossref] [Google Scholar]
  53. Ferrer M, Anthony TG, Ayres JS, Biffi G, Brown JC, et al. 2023.. Cachexia: a systemic consequence of progressive, unresolved disease. . Cell 186:(9):182445
    [Crossref] [Google Scholar]
  54. Flowers BM, Xu H, Mulligan AS, Hanson KJ, Seoane JA, et al. 2021.. Cell of origin influences pancreatic cancer subtype. . Cancer Discov. 11:(3):66077
    [Crossref] [Google Scholar]
  55. Friedlander SYG, Chu GC, Snyder EL, Girnius N, Dibelius G, et al. 2009.. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. . Cancer Cell 16:(5):37989
    [Crossref] [Google Scholar]
  56. Genovese G, Carugo A, Tepper J, Robinson FS, Li L, et al. 2017.. Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer. . Nature 542:(7641):36266
    [Crossref] [Google Scholar]
  57. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, et al. 2020.. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. . Gut 69:(1):717. Erratum . 2020.. Gut 69:(6):e3
    [Google Scholar]
  58. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, et al. 2019.. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. . New Engl. J. Med. 381:(4):31727
    [Crossref] [Google Scholar]
  59. González-Gómez R, Pazo-Cid RA, Sarría L, Morcillo , Schuhmacher AJ. 2021.. Diagnosis of pancreatic ductal adenocarcinoma by immuno-positron emission tomography. . J. Clin. Med. 10:(6):1151
    [Crossref] [Google Scholar]
  60. Groot VP, Rezaee N, Wu W, Cameron JL, Fishman EK, et al. 2018.. Patterns, timing, and predictors of recurrence following pancreatectomy for pancreatic ductal adenocarcinoma. . Ann. Surg. 267:(5):93645
    [Crossref] [Google Scholar]
  61. Grossberg AJ, Chu LC, Deig CR, Fishman EK, Hwang WL, et al. 2020.. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. . CA Cancer J. Clin. 70:(5):375403
    [Crossref] [Google Scholar]
  62. Grünwald BT, Devisme A, Andrieux G, Vyas F, Aliar K, et al. 2021.. Spatially confined sub-tumor microenvironments in pancreatic cancer. . Cell 184:(22):557792.e18
    [Crossref] [Google Scholar]
  63. Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L, et al. 2007.. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. . Cancer Cell 11:(3):291302
    [Crossref] [Google Scholar]
  64. Guler GD, Ning Y, Ku CJ, Phillips T, McCarthy E, et al. 2020.. Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA. . Nat. Commun. 11:(1):5270
    [Crossref] [Google Scholar]
  65. Hallin J, Bowcut V, Calinisan A, Briere DM, Hargis L, et al. 2022.. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. . Nat. Med. 28:(10):217182
    [Crossref] [Google Scholar]
  66. Han J, Xu J, Liu Y, Liang S, LaBella KA, et al. 2023.. Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. . Genes Dev. 37:(17–18):81828
    [Crossref] [Google Scholar]
  67. Hausmann S, Kong B, Michalski C, Erkan M, Friess H. 2014.. The role of inflammation in pancreatic cancer. . Adv. Exp. Med. Biol. 816::12951
    [Crossref] [Google Scholar]
  68. Hayashi A, Fan J, Chen R, Ho Y, Makohon-Moore AP, et al. 2020.. A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma. . Nat. Cancer 1:(1):5974
    [Crossref] [Google Scholar]
  69. Hayashi A, Hong J, Iacobuzio-Donahue CA. 2021.. The pancreatic cancer genome revisited. . Nat. Rev. Gastroenterol. Hepatol. 18:(7):46981
    [Crossref] [Google Scholar]
  70. Hegde S, Krisnawan VE, Herzog BH, Zuo C, Breden MA, et al. 2020.. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. . Cancer Cell 37:(3):289307.e9
    [Crossref] [Google Scholar]
  71. Hermann PC, Sancho P, Cañamero M, Martinelli P, Madriles F, et al. 2014.. Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice. . Gastroenterology 147:(5):111933.e4
    [Crossref] [Google Scholar]
  72. Hosein AN, Brekken RA, Maitra A. 2020.. Pancreatic cancer stroma: an update on therapeutic targeting strategies. . Nat. Rev. Gastroenterol. Hepatol. 17:(8):487505
    [Crossref] [Google Scholar]
  73. Hoshino A, Kim HS, Bojmar L, Gyan KE, Cioffi M, et al. 2020.. Extracellular vesicle and particle biomarkers define multiple human cancers. . Cell 182:(4):104461.e18
    [Crossref] [Google Scholar]
  74. Hou P, Kapoor A, Zhang Q, Li J, Wu CJ, et al. 2020.. Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer. . Cancer Discov. 10:(7):105877
    [Crossref] [Google Scholar]
  75. Hou P, Ma X, Yang Z, Zhang Q, Wu CJ, et al. 2021.. USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer. . Genes Dev. 35:(19):132732
    [Crossref] [Google Scholar]
  76. Huang H, Wang Z, Zhang Y, Pradhan RN, Ganguly D, et al. 2022.. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. . Cancer Cell 40:(6):65673.e7
    [Crossref] [Google Scholar]
  77. Hwang WL, Jagadeesh KA, Guo JA, Hoffman HI, Yadollahpour P, et al. 2022.. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. . Nat. Genet. 54:(8):117891
    [Crossref] [Google Scholar]
  78. Ji B, Tsou L, Wang H, Gaiser S, Chang DZ, et al. 2009.. Ras activity levels control the development of pancreatic diseases. . Gastroenterology 137:(3):107282.e6
    [Crossref] [Google Scholar]
  79. Jiang H, Torphy RJ, Steiger K, Hongo H, Ritchie AJ, et al. 2020.. Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. . J. Clin. Investig. 130:(9):47049
    [Crossref] [Google Scholar]
  80. Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W, et al. 2015.. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. . Cancer Res. 75:(3):54453
    [Crossref] [Google Scholar]
  81. Kapoor A, Yao W, Ying H, Hua S, Liewen A, et al. 2014.. Yap1 activation enables bypass of oncogenic KRAS addiction in pancreatic cancer. . Cell 158:(1):18597
    [Crossref] [Google Scholar]
  82. Kays JK, Shahda S, Stanley M, Bell TM, O'Neill BH, et al. 2018.. Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer. . J. Cachexia Sarcopenia Muscle 9:(4):67384
    [Crossref] [Google Scholar]
  83. Kemp SB, Cheng N, Markosyan N, Sor R, Kim IK, et al. 2023.. Efficacy of a small-molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer. . Cancer Discov. 13:(2):298311
    [Crossref] [Google Scholar]
  84. Klein AP. 2021.. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. . Nat. Rev. Gastroenterol. Hepatol. 18:(7):493502
    [Crossref] [Google Scholar]
  85. Kloesch B, Ionasz V, Paliwal S, Hruschka N, Martinez De Villarreal J, et al. 2022.. A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer. . Gut 71:(4):76677
    [Crossref] [Google Scholar]
  86. Knox JJ, Jaffee EM, O'Kane GM, Plenker D, Zhang A, et al. 2022.. PASS-01: pancreatic adenocarcinoma signature stratification for treatment-01. . J. Clin. Oncol. 40:(4):TPS635
    [Crossref] [Google Scholar]
  87. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, et al. 2010.. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. . Science 330:(6005):82730
    [Crossref] [Google Scholar]
  88. Lan L, Evan T, Li H, Hussain A, Ruiz EJ, et al. 2022.. GREM1 is required to maintain cellular heterogeneity in pancreatic cancer. . Nature 607:(7917):16368
    [Crossref] [Google Scholar]
  89. Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, et al. 2020.. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. . Ann. Oncol. 31:(6):74559
    [Crossref] [Google Scholar]
  90. Liudahl SM, Betts CB, Sivagnanam S, Morales-Oyarvide V, Da Silva A, et al. 2021.. Leukocyte heterogeneity in pancreatic ductal adenocarcinoma: phenotypic and spatial features associated with clinical outcome. . Cancer Discov. 11:(8):201431
    [Crossref] [Google Scholar]
  91. Lohrmann C, O'Reilly EM, O'Donoghue JA, Pandit-Taskar N, Carrasquillo JA, et al. 2019.. Retooling a blood-based biomarker: phase I assessment of the high-affinity CA19-9 antibody HuMab-5B1 for immuno-PET imaging of pancreatic cancer. . Clin. Cancer Res. 25:(23):701423
    [Crossref] [Google Scholar]
  92. Mahadevan KK, McAndrews KM, LeBleu VS, Yang S, Lyu H, et al. 2023.. KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells. . Cancer Cell 41:(9):160620.e8
    [Crossref] [Google Scholar]
  93. Maitra A, Sharma A, Brand RE, Van Den Eeden SK, Fisher WE, et al. 2018.. A prospective study to establish a new-onset diabetes cohort: from the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. . Pancreas 47:(10):124448
    [Crossref] [Google Scholar]
  94. Makohon-Moore AP, Zhang M, Reiter JG, Bozic I, Allen B, et al. 2017.. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. . Nat. Genet. 49:(3):35866
    [Crossref] [Google Scholar]
  95. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, de Jesus-Acosta A, et al. 2020.. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. . J. Clin. Oncol. 38:(1):110
    [Crossref] [Google Scholar]
  96. McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, et al. 2017.. Large-scale epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. . Nat. Genet. 49:(3):36776
    [Crossref] [Google Scholar]
  97. Miyabayashi K, Baker LA, Deschênes A, Traub B, Caligiuri G, et al. 2020.. Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes. . Cancer Discov. 10:(10):156689
    [Crossref] [Google Scholar]
  98. Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SGH, et al. 2015.. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. . Nat. Genet. 47:(10):116878
    [Crossref] [Google Scholar]
  99. Morris JP, Yashinskie JJ, Koche R, Chandwani R, Tian S, et al. 2019.. α-Ketoglutarate links p53 to cell fate during tumour suppression. . Nature 573:(7775):59599
    [Crossref] [Google Scholar]
  100. Mundi PS, Dela Cruz FS, Grunn A, Diolaiti D, Mauguen A, et al. 2023.. Transcriptome-based precision oncology platform for patient-therapy alignment in a diverse set of treatment-resistant malignancies. . Cancer Discov. 13:(6):1386407
    [Crossref] [Google Scholar]
  101. Murthy D, Attri KS, Shukla SK, Thakur R, Chaika NV, et al. 2024.. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis. . Nat. Cell Biol. 26:(4):61327
    [Crossref] [Google Scholar]
  102. Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, et al. 2017.. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. . J. Exp. Med. 214:(3):57996
    [Crossref] [Google Scholar]
  103. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, et al. 2009.. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. . Science 324:(5933):145761
    [Crossref] [Google Scholar]
  104. Oni TE, Bautista C, Merrill JR, Goos JACM, Rivera KD, et al. 2020a.. Detection of incipient pancreatic cancer with novel tumor-specific antibodies in mouse models. . bioRxiv 2020.09.10.292193. https://doi.org/10.1101/2020.09.10.292193
  105. Oni TE, Biffi G, Baker LA, Hao Y, Tonelli C, et al. 2020b.. SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. . J. Exp. Med. 217:(9):e20192389
    [Crossref] [Google Scholar]
  106. Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, et al. 2014.. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with diminished survival. . Cancer Cell 25:(6):71934
    [Crossref] [Google Scholar]
  107. Park W, Chawla A, O'Reilly EM. 2021.. Pancreatic cancer: a review. . JAMA 326:(9):85162
    [Crossref] [Google Scholar]
  108. Pavlova NN, Zhu J, Thompson CB. 2022.. The hallmarks of cancer metabolism: still emerging. . Cell Metab. 34:(3):35577
    [Crossref] [Google Scholar]
  109. Philip B, Roland CL, Daniluk J, Liu Y, Chatterjee D, et al. 2013.. A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. . Gastroenterology 145:(6):144958
    [Crossref] [Google Scholar]
  110. Pishvaian MJ, Blais EM, Brody JR, Lyons E, DeArbeloa P, et al. 2020.. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. . Lancet Oncol. 21:(4):50818
    [Crossref] [Google Scholar]
  111. Pitter KL, Grbovic-Huezo O, Joost S, Singhal A, Blum M, et al. 2022.. Systematic comparison of pancreatic ductal adenocarcinoma models identifies a conserved highly plastic basal cell state. . Cancer Res. 82:(19):354960
    [Google Scholar]
  112. Placido D, Yuan B, Hjaltelin JX, Zheng C, Haue AD, et al. 2023.. A deep learning algorithm to predict risk of pancreatic cancer from disease trajectories. . Nat. Med. 29:(5):111322
    [Crossref] [Google Scholar]
  113. Raghavan S, Winter PS, Navia AW, Williams HL, DenAdel A, et al. 2021.. Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer. . Cell 184:(25):611937.e26
    [Crossref] [Google Scholar]
  114. Rashid NU, Peng XL, Jin C, Moffitt RA, Volmar KE, et al. 2020.. Purity Independent Subtyping of Tumors (PurIST), a clinically robust, single sample classifier for tumor subtyping in pancreatic cancer. . Clin. Cancer Res. 26:(1):8292
    [Crossref] [Google Scholar]
  115. Recouvreux MV, Moldenhauer MR, Galenkamp KMO, Jung M, James B, et al. 2020.. Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer. . J. Exp. Med. 217:(9):e20200388
    [Crossref] [Google Scholar]
  116. Reichert M, Bakir B, Moreira L, Pitarresi JR, Feldmann K, et al. 2018.. Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer. . Dev. Cell 45:(6):696711.e8
    [Crossref] [Google Scholar]
  117. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, et al. 2012.. EMT and dissemination precede pancreatic tumor formation. . Cell 148:(1–2):34961
    [Crossref] [Google Scholar]
  118. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, et al. 2014.. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. . Cancer Cell 25:(6):73547
    [Crossref] [Google Scholar]
  119. Roe JS, Hwang C-I, Somerville TDD, Milazzo JP, Lee EJ, et al. 2017.. Enhancer reprogramming promotes pancreatic cancer metastasis. . Cell 170:(5):87588.e20
    [Crossref] [Google Scholar]
  120. Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, et al. 2023.. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. . Nature 618:(7963):14450
    [Crossref] [Google Scholar]
  121. Ruiz CF, Garcia C, Jacox JB, Lawres L, Muzumdar MD. 2023.. Decoding the obesity-cancer connection: lessons from preclinical models of pancreatic adenocarcinoma. . Life Sci. Alliance 6:(11):e202302228
    [Crossref] [Google Scholar]
  122. Saloman JL, Albers KM, Cruz-Monserrate Z, Davis BM, Edderkaoui M, et al. 2019.. Animal models: challenges and opportunities to determine optimal experimental models of pancreatitis and pancreatic cancer. . Pancreas 48:(6):75979
    [Crossref] [Google Scholar]
  123. Schwörer S, Pavlova NN, Cimino FV, King B, Cai X, et al. 2021.. Fibroblast pyruvate carboxylase is required for collagen production in the tumor microenvironment. . Nat. Metab. 3:(11):148499
    [Crossref] [Google Scholar]
  124. Sharma A, Smyrk TC, Levy MJ, Topazian MA, Chari ST. 2018.. Fasting blood glucose levels provide estimate of duration and progression of pancreatic cancer before diagnosis. . Gastroenterology 155:(2):490500.e2
    [Crossref] [Google Scholar]
  125. Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, et al. 2014.. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. . Cell 159:(1):8093
    [Crossref] [Google Scholar]
  126. Siegel RL, Giaquinto AN, Jemal A. 2024.. Cancer statistics, 2024. . CA Cancer J. Clin. 74:(1):1249
    [Crossref] [Google Scholar]
  127. Simeonov KP, Byrns CN, Clark ML, Norgard RJ, Martin B, et al. 2021.. Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states. . Cancer Cell 39:(8):115062.e9
    [Crossref] [Google Scholar]
  128. Singhal A, Li BT, O'Reilly EM. 2024.. Targeting KRAS in cancer. . Nat. Med. 30:(4):96983
    [Crossref] [Google Scholar]
  129. Singhi AD, Wood LD. 2021.. Early detection of pancreatic cancer using DNA-based molecular approaches. . Nat. Rev. Gastroenterol. Hepatol. 18:(7):45768
    [Crossref] [Google Scholar]
  130. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, et al. 2013.. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. . Nature 496:(7443):1015
    [Crossref] [Google Scholar]
  131. Sousa CM, Biancur DE, Wang X, Halbrook CJ, Sherman MH, et al. 2016.. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. . Nature 536:(7617):47983
    [Crossref] [Google Scholar]
  132. Steele NG, Biffi G, Kemp SB, Zhang Y, Drouillard D, et al. 2021.. Inhibition of Hedgehog signaling alters fibroblast composition in pancreatic cancer. . Clin. Cancer Res. 27:(7):202337
    [Crossref] [Google Scholar]
  133. Stoffel EM, Brand RE, Goggins M. 2023.. Pancreatic cancer: changing epidemiology and new approaches to risk assessment, early detection, and prevention. . Gastroenterology 164:(5):75265
    [Crossref] [Google Scholar]
  134. Stone ML, Beatty GL. 2019.. Cellular determinants and therapeutic implications of inflammation in pancreatic cancer. . Pharmacol. Ther. 201::20213
    [Crossref] [Google Scholar]
  135. Tiriac H, Belleau P, Engle DD, Plenker D, Deschênes A, et al. 2018.. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. . Cancer Discov. 8:(9):111229
    [Crossref] [Google Scholar]
  136. Tonelli C, Yordanov GN, Hao Y, Deschênes A, Hinds J, et al. 2024.. A mucus production programme promotes classical pancreatic ductal adenocarcinoma. . Gut 73::94154
    [Crossref] [Google Scholar]
  137. Trikudanathan G, Lou E, Maitra A, Majumder S. 2021.. Early detection of pancreatic cancer: current state and future opportunities. . Curr. Opin. Gastroenterol. 37:(5):53238
    [Crossref] [Google Scholar]
  138. Tu M, Klein L, Espinet E, Georgomanolis T, Wegwitz F, et al. 2021.. TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer. . Nat. Cancer 2:(11):1185203
    [Crossref] [Google Scholar]
  139. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, et al. 2014.. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. . Nature 514:(7524):62832
    [Crossref] [Google Scholar]
  140. Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, et al. 2024.. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. . Nature 629:(8013):92736
    [Crossref] [Google Scholar]
  141. Westphalen CB, Olive KP. 2012.. Genetically engineered mouse models of pancreatic cancer. . Cancer J. 18:(6):50210
    [Crossref] [Google Scholar]
  142. Williams HL, Costa AD, Zhang J, Raghavan S, Winter PS, et al. 2023.. Spatially resolved single-cell assessment of pancreatic cancer expression subtypes reveals co-expressor phenotypes and extensive intra-tumoral heterogeneity. . Cancer Res. 83:(3):44155
    [Crossref] [Google Scholar]
  143. Wittel UA, Pandey KK, Andrianifahanana M, Johansson SL, Cullen DM, et al. 2006.. Chronic pancreatic inflammation induced by environmental tobacco smoke inhalation in rats. . Am. J. Gastroenterol. 101:(1):14859
    [Crossref] [Google Scholar]
  144. Yang S, Wang X, Contino G, Liesa M, Sahin E, et al. 2011.. Pancreatic cancers require autophagy for tumor growth. . Genes Dev. 25:(7):71729
    [Crossref] [Google Scholar]
  145. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, et al. 2012.. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. . Cell 149:(3):65670
    [Crossref] [Google Scholar]
  146. Yousuf S, Qiu M, Voith von Voithenberg L, Hulkkonen J, Macinkovic I, et al. 2023.. Spatially resolved multi-omics single-cell analyses inform mechanisms of immune dysfunction in pancreatic cancer. . Gastroenterology 165:(4):891908.e14
    [Crossref] [Google Scholar]
  147. Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, et al. 2009.. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. . Science 325:(5947):155559
    [Crossref] [Google Scholar]
  148. Zhang AMY, Xia YH, Lin JSH, Chu KH, Wang WCK, et al. 2023.. Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation. . Cell Metab. 35:(12):211935.e5
    [Crossref] [Google Scholar]
  149. Zhang Y, Arner EN, Rizvi A, Toombs JE, Huang H, et al. 2022.. AXL inhibitor TP-0903 reduces metastasis and therapy resistance in pancreatic cancer. . Mol. Cancer Ther. 21:(1):3847
    [Crossref] [Google Scholar]
  150. Zhu XG, Chudnovskiy A, Baudrier L, Prizer B, Liu Y, et al. 2021.. Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells. . Cell Metab. 33:(1):21121.e6
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-060624-044323
Loading
/content/journals/10.1146/annurev-cancerbio-060624-044323
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error