REFERENCES
4. Hayashi A, Hong J, Iacobuzio-Donahue CA. The pancreatic cancer genome revisited. Nat Rev Gastroenterol Hepatol 2021;18:469-81.
5. Kopp JL, von Figura G, Mayes E, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 2012;22:737-50.
6. Guerra C, Schuhmacher AJ, Cañamero M, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007;11:291-302.
7. Giroux V, Rustgi AK. Metaplasia: tissue injury adaptation and a precursor to the dysplasia-cancer sequence. Nat Rev Cancer 2017;17:594-604.
8. Storz P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 2017;14:296-304.
9. Morris JP 4th, Cano DA, Sekine S, Wang SC, Hebrok M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest 2010;120:508-20.
10. Li Y, He Y, Peng J, et al. Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer. Nat Cancer 2021;2:49-65.
11. Gidekel Friedlander SY, Chu GC, Snyder EL, et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 2009;16:379-89.
12. Bailey JM, Hendley AM, Lafaro KJ, et al. p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. Oncogene 2016;35:4282-8.
13. Ferreira RMM, Sancho R, Messal HA, et al. Duct- and acinar-derived pancreatic ductal adenocarcinomas show distinct tumor progression and marker expression. Cell Rep 2017;21:966-78.
14. Morris JP 4th, Hebrok M. It’s a free for all-insulin-positive cells join the group of potential progenitors for pancreatic ductal adenocarcinoma. Cancer Cell 2009;16:359-61.
15. Collisson EA, Sadanandam A, Olson P, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 2011;17:500-3.
16. Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet 2015;47:1168-78.
17. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016;531:47-52.
18. Luchini C, Capelli P, Scarpa A. Pancreatic ductal adenocarcinoma and its variants. Surg Pathol Clin 2016;9:547-60.
19. Niger M, Prisciandaro M, Antista M, et al. One size does not fit all for pancreatic cancers: A review on rare histologies and therapeutic approaches. World J Gastrointest Oncol 2020;12:833-49.
20. Genome Atlas Research Network. Electronic address: [email protected]., Cancer Genome Atlas Research Network. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 2017;32:185-203.e13.
21. Puleo F, Nicolle R, Blum Y, et al. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology 2018;155:1999-2013.e3.
22. Maurer C, Holmstrom SR, He J, et al. Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes. Gut 2019;68:1034-43.
23. Chan-Seng-Yue M, Kim JC, Wilson GW, et al. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. Nat Genet 2020;52:231-40.
24. Raghavan S, Winter PS, Navia AW, et al. Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer. Cell 2021;184:6119-6137.e26.
25. O’Kane GM, Grünwald BT, Jang GH, et al. GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer. Clin Cancer Res 2020;26:4901-10.
26. Aguirre AJ, Bardeesy N, Sinha M, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003;17:3112-26.
27. Mueller S, Engleitner T, Maresch R, et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 2018;554:62-8.
28. Lee AYL, Dubois CL, Sarai K, et al. Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma. Gut 2019;68:487-98.
29. Flowers BM, Xu H, Mulligan AS, et al. Cell of origin influences pancreatic cancer subtype. Cancer Discov 2021;11:660-77.
30. Martens S, Coolens K, Van Bulck M, et al. Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease. Gut 2021:gutjnl-2020.
31. Krieger TG, Le Blanc S, Jabs J, et al. Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy. Nat Commun 2021;12:5826.
32. Miyabayashi K, Baker LA, Deschênes A, et al. Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes. Cancer Discov 2020;10:1566-89.
33. Candido JB, Morton JP, Bailey P, et al. CSF1R+ macrophages sustain pancreatic tumor growth through T Cell suppression and maintenance of key gene programs that define the squamous subtype. Cell Rep 2018;23:1448-60.
34. Tu M, Klein L, Espinet E, et al. TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer. Nat Cancer 2021;2:1185-203.
35. Collins MA, Brisset JC, Zhang Y, et al. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLoS One 2012;7:e49707.
36. Ying H, Kimmelman AC, Lyssiotis CA, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012;149:656-70.
37. Martinelli P, Cañamero M, del Pozo N, Madriles F, Zapata A, Real FX. Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice. Gut 2013;62:1481-8.
38. Andricovich J, Perkail S, Kai Y, Casasanta N, Peng W, Tzatsos A. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to bet inhibitors. Cancer Cell 2018;33:512-526.e8.
39. Fu B, Luo M, Lakkur S, Lucito R, Iacobuzio-Donahue CA. Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma. Cancer Biol Ther 2008;7:1593-601.
40. Kwei KA, Bashyam MD, Kao J, et al. Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer. PLoS Genet 2008;4:e1000081.
41. Garraway LA, Sellers WR. Lineage dependency and lineage-survival oncogenes in human cancer. Nat Rev Cancer 2006;6:593-602.
42. Aung KL, Fischer SE, Denroche RE, et al. Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial. Clin Cancer Res 2018;24:1344-54.
43. Martinelli P, Carrillo-de Santa Pau E, Cox T, et al. GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut 2017;66:1665-76.
44. Brunton H, Caligiuri G, Cunningham R, et al. HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer. Cell Rep 2020;31:107625.
45. Kloesch B, Ionasz V, Paliwal S, et al. A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer. Gut 2022;71:766-77.
46. Allen HL, Flanagan SE, Shaw-Smith C, et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet 2011;44:20-2.
47. Shi ZD, Lee K, Yang D, et al. Genome editing in hPSCs reveals GATA6 haploinsufficiency and a genetic interaction with GATA4 in human pancreatic development. Cell Stem Cell 2017;20:675-688.e6.
48. Carrasco M, Delgado I, Soria B, Martín F, Rojas A. GATA4 and GATA6 control mouse pancreas organogenesis. J Clin Invest 2012;122:3504-15.
49. Camolotto SA, Belova VK, Torre-Healy L, et al. Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Gut 2021;70:900-14.
50. Daemen A, Peterson D, Sahu N, et al. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc Natl Acad Sci USA 2015;112:E4410-7.
51. Kalisz M, Bernardo E, Beucher A, et al. HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer. EMBO J 2020;39:e102808.
52. Abel EV, Goto M, Magnuson B, et al. HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties. Elife 2018;7:e33947.
53. Diaferia GR, Balestrieri C, Prosperini E, et al. Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer. EMBO J 2016;35:595-617.
54. Diaferia GR, Natoli G. Transcription factors as drivers of distinct pancreatic ductal adenocarcinoma (PDAC) programmes: a role for HNF4A. Gut 2021;70:816-7.
55. He P, Yang JW, Yang VW, Bialkowska AB. Krüppel-like factor 5, increased in pancreatic ductal adenocarcinoma, promotes proliferation, acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia, and tumor growth in mice. Gastroenterology 2018;154:1494-1508.e13.
56. Alfarano G, Audano M, Di Chiaro P, et al. Interferon regulatory factor 1 (IRF1) controls the metabolic programmes of low-grade pancreatic cancer cells. Gut ;2022:gutjnl-2021.
57. Somerville TDD, Xu Y, Wu XS, et al. ZBED2 is an antagonist of interferon regulatory factor 1 and modifies cell identity in pancreatic cancer. Proc Natl Acad Sci USA 2020;117:11471-82.
58. Tonelli C, Yordanov GN, Hao Y, et al. SPDEF promotes the classical subtype of pancreatic ductal adenocarcinoma. bioRxiv 2022:2022.03.18.484951.
59. Steiner S, Seleznik GM, Reding T, et al. De novo expression of gastrokines in pancreatic precursor lesions impede the development of pancreatic cancer. Oncogene 2022;41:1507-17.
60. Ganguly K, Krishn SR, Rachagani S, et al. Secretory Mucin 5AC promotes neoplastic progression by augmenting KLF4-mediated pancreatic cancer cell stemness. Cancer Res 2021;81:91-102.
61. Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer 2014;14:581-97.
62. Bujalka H, Koenning M, Jackson S, et al. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol 2013;11:e1001625.
63. Li Z, Park Y, Marcotte EM. A Bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF. PLoS Biol 2013;11:e1001624.
64. Milan M, Balestrieri C, Alfarano G, et al. Pancreatic Cancer Cells require the Transcription Factor MYRF to maintain ER homeostasis. Dev Cell 2020;55:398-412.e7.
65. Gregorieff A, Stange DE, Kujala P, et al. The ets-domain transcription factor Spdef promotes maturation of goblet and paneth cells in the intestinal epithelium. Gastroenterology 2009;137:1333-45.e1.
66. Chen G, Korfhagen TR, Xu Y, et al. SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production. J Clin Invest 2009;119:2914-24.
67. Higa A, Mulot A, Delom F, et al. Role of pro-oncogenic protein disulfide isomerase (PDI) family member anterior gradient 2 (AGR2) in the control of endoplasmic reticulum homeostasis. J Biol Chem 2011;286:44855-68.
68. Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 1998;12:1812-24.
69. Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 1998;17:5708-17.
70. David CJ, Huang YH, Chen M, et al. TGF-β tumor suppression through a lethal EMT. Cell 2016;164:1015-30.
71. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999;398:708-13.
72. Soares E, Zhou H. Master regulatory role of p63 in epidermal development and disease. Cell Mol Life Sci 2018;75:1179-90.
73. Rocco JW, Leong CO, Kuperwasser N, DeYoung MP, Ellisen LW. p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 2006;9:45-56.
74. Patturajan M, Nomoto S, Sommer M, et al. ΔNp63 induces β-catenin nuclear accumulation and signaling. Cancer Cell 2002;1:369-79.
75. Jiang YY, Jiang Y, Li CQ, et al. TP63, SOX2, and KLF5 establish a core regulatory circuitry that controls epigenetic and transcription patterns in esophageal squamous cell carcinoma cell lines. Gastroenterology 2020;159:1311-1327.e19.
76. Somerville TDD, Xu Y, Miyabayashi K, et al. TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma. Cell Rep 2018;25:1741-1755.e7.
77. Hamdan FH, Johnsen SA. DeltaNp63-dependent super enhancers define molecular identity in pancreatic cancer by an interconnected transcription factor network. Proc Natl Acad Sci USA 2018;115:E12343-52.
