The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

eLife

Volumn 4, Issue JULY2015, 2015, Pages

  Krah, Nathan M ^a   De La O , Jean Paul ^a   Swift, Galvin H ^b   Hoang, Chinh Q ^b   Willet, Spencer G ^c   Pan, Fong Chen ^c   Cash, Gabriela M ^a   Bronner, Mary P ^a   Wright, Christopher V E ^c   MacDonald, Raymond J ^b   Murtaugh, L Charles ^a  

^a UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACINAR CELL; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER GROWTH; CELL DIFFERENTIATION; CELL TRANSFORMATION; CONTROLLED STUDY; GENE MUTATION; GENOTYPE; HETEROZYGOSITY; HUMAN; IMMUNOFLUORESCENCE; IMMUNOHISTOCHEMISTRY; KAPLAN MEIER METHOD; METAPLASIA; MOUSE; NONHUMAN; PANCREAS ADENOCARCINOMA; SIGNAL TRANSDUCTION; ADENOCARCINOMA; ANIMAL; CARCINOMA IN SITU; CELL TRANSDIFFERENTIATION; DISEASE MODEL; GENE EXPRESSION PROFILING; GENETICS; PANCREAS CARCINOMA; PATHOLOGY; PHYSIOLOGY;

MUS;

TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR PTF1;

ACINAR CELLS; ADENOCARCINOMA; ANIMALS; CARCINOMA IN SITU; CARCINOMA, PANCREATIC DUCTAL; CELL TRANSDIFFERENTIATION; DISEASE MODELS, ANIMAL; GENE EXPRESSION PROFILING; HUMANS; MICE; TRANSCRIPTION FACTORS;

EID: 84939540291     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.07125.001     Document Type: Article

References (85)

1. Adrian K, Strouch MJ, Zeng Q, Barron MR, Cheon EC, Honasoge A, Xu Y, Phukan S, Sadim M, Bentrem DJ, Pasche B, Grippo PJ. 2009. Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer. Cancer Research 69: 9169-9174. doi: 10. 1158/0008-5472. CAN-09-1705.
2. Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, Redston MS, DePinho RA. 2003. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes & Development 17: 3112-3126. doi: 10. 1101/gad. 1158703.
3. Ardito CM, Gruner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, Pal D, Briel T, Herner A, Trajkovic-Arsic M, Sipos B, Liou GY, Storz P, Murray NR, Threadgill DW, Sibilia M, Washington MK, Wilson CL, Schmid RM, Raines EW, Crawford HC, Siveke JT. 2012. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22: 304-317. doi: 10. 1016/j. ccr. 2012. 07. 024.
4. Baer R, Cintas C, Dufresne M, Cassant-Sourdy S, Schonhuber N, Planque L, Lulka H, Couderc B, Bousquet C, Garmy-Susini B, Vanhaesebroeck B, Pyronnet S, Saur D, Guillermet-Guibert J. 2014. Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110alpha. Genes & Development 28: 2621-2635. doi: 10. 1101/gad. 249409. 114.
5. Bailey JM, DelGiorno KE, Crawford HC. 2014. The secret origins and surprising fates of pancreas tumors. Carcinogenesis 35: 1436-1440. doi: 10. 1093/carcin/bgu056.
6. Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, DePinho RA. 2006. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes & Development 20: 3130-3146. doi: 10. 1101/gad. 1478706.
7. Bedrosian AS, Nguyen AH, Hackman M, Connolly MK, Malhotra A, Ibrahim J, Cieza-Rubio NE, Henning JR, Barilla R, Rehman A, Pachter HL, Medina-Zea MV, Cohen SM, Frey AB, Acehan D, Miller G. 2011. Dendritic cells promote pancreatic viability in mice with acute pancreatitis. Gastroenterology 141: 1915-1926. e14. doi: 10. 1053/j. gastro. 2011. 07. 033.
8. Blanpain C. 2013. Tracing the cellular origin of cancer. Nature Cell Biology 15: 126-134. doi: 10. 1038/ncb2657.
9. Bockman DE, Boydston WR, Anderson MC. 1982. Origin of tubular complexes in human chronic pancreatitis. American Journal of Surgery 144: 243-249. doi: 10. 1016/0002-9610(82)90518-9.
10. Boj SF, Hwang CI, Baker LA, Chio II, Engle DD, Corbo V, Jager M, Ponz-Sarvise M, Tiriac H, Spector MS, Gracanin A, Oni T, Yu KH, van Boxtel R, Huch M, Rivera KD, Wilson JP, Feigin ME, Öhlund D, Handly-Santana A, Ardito-Abraham CM, Ludwig M, Elyada E, Alagesan B, Biffi G, Yordanov GN, Delcuze B, Creighton B, Wright K, Park Y, Morsink FH, Molenaar IQ, Borel Rinkes IH, Cuppen E, Hao Y, Jin Y, Nijman IJ, Iacobuzio-Donahue C, Leach SD, Pappin DJ, Hammell M, Klimstra DS, Basturk O, Hruban RH, Offerhaus GJ, Vries RG, Clevers H, Tuveson DA. 2015. Organoid models of human and mouse ductal pancreatic cancer. Cell 160: 324-338. doi: 10. 1016/j. cell. 2014. 12. 021.
11. Brune K, Abe T, Canto M, O'Malley L, Klein AP, Maitra A, Volkan Adsay N, Fishman EK, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH. 2006. Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. The American Journal of Surgical Pathology 30: 1067-1076.
12. Collins MA, Yan W, Sebolt-Leopold JS, Pasca di Magliano M. 2014. MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology 146: 822-834. e7. doi: 10. 1053/j. gastro. 2013. 11. 052.
13. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L, Feiler HS, Ko AH, Olshen AB, Danenberg KL, Tempero MA, Spellman PT, Hanahan D, Gray JW. 2011. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nature Medicine 17: 500-503. doi: 10. 1038/nm. 2344.
14. Daniluk J, Liu Y, Deng D, Chu J, Huang H, Gaiser S, Cruz-Monserrate Z, Wang H, Ji B, Logsdon CD. 2012. An NFkappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. The Journal of Clinical Investigation 122: 1519-1528. doi: 10. 1172/JCI59743.
15. De La O JP, Emerson LL, Goodman JL, Froebe SC, Illum BE, Curtis AB, Murtaugh LC. 2008. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proceedings of the National Academy of Sciences of USA 105: 18907-18912. doi: 10. 1073/pnas. 0810111105.
16. Erkan M, Adler G, Apte MV, Bachem MG, Buchholz M, Detlefsen S, Esposito I, Friess H, Gress TM, Habisch HJ, Hwang RF, Jaster R, Kleeff J, Klöppel G, Kordes C, Logsdon CD, Masamune A, Michalski CW, Oh J, Phillips PA, Pinzani M, Reiser-Erkan C, Tsukamoto H, Wilson J. 2012. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61: 172-178. doi: 10. 1136/gutjnl-2011-301220.
17. Flandez M, Cendrowski J, Canamero M, Salas A, del Pozo N, Schoonjans K, Real FX. 2014. Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRas(G12V)-driven pancreatic tumourigenesis. Gut 63: 647-655. doi: 10. 1136/gutjnl-2012-304381.
18. Gore AJ, Deitz SL, Palam LR, Craven KE, Korc M. 2014. Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-beta to promote proliferation. The Journal of Clinical Investigation 124: 338-352. doi: 10. 1172/JCI71526.
19. Gu G, Dubauskaite J, Melton DA. 2002. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129: 2447-2457.
20. Gukovsky I, Li N, Todoric J, Gukovskaya A, Karin M. 2013. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 144: 1199-1209. e4. doi: 10. 1053/j. gastro. 2013. 02. 007.
21. Gurdon JB, Lemaire P, Kato K. 1993. Community effects and related phenomena in development. Cell 75: 831-834. doi: 10. 1016/0092-8674(93)90526-V.
22. Habbe N, Shi G, Meguid RA, Fendrich V, Esni F, Chen H, Feldmann G, Stoffers DA, Konieczny SF, Leach SD, Maitra A. 2008. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proceedings of the National Academy of Sciences of USA 105: 18913-18918. doi: 10. 1073/pnas. 0810097105.
23. Harris H. 1990. The role of differentiation in the suppression of malignancy. Journal of Cell Science 97: 5-10.
24. Hayashi S, Tenzen T, McMahon AP. 2003. Maternal inheritance of Cre activity in a Sox2Cre deleter strain. Genesis 37: 51-53. doi: 10. 1002/gene. 10225.
25. Heid I, Lubeseder-Martellato C, Sipos B, Mazur PK, Lesina M, Schmid RM, Siveke JT. 2011. Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology 141: 719-730. 730. e1-7. doi: 10. 1053/j. gastro. 2011. 04. 043.
26. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA. 2003. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4: 437-450. doi: 10. 1016/S1535-6108(03)00309-X.
27. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. 2005. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7: 469-483. doi: 10. 1016/j. ccr. 2005. 04. 023.
28. Hoang C, Swift GH, Azevedo-Pouly A, MacDonald RJ. 2015. Effects on the transcriptome of adult mouse pancreas (principally acinar cells) by the inactivation of the Ptf1a gene in vivo. NCBI Gene Expression Omnibus GSE70542. http://www. ncbi. nlm. nih. gov/geo/query/acc. cgi?acc=GSE70542.
29. Holmstrom SR, Deering T, Swift GH, Poelwijk FJ, Mangelsdorf DJ, Kliewer SA, MacDonald RJ. 2011. LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function. Genes & Development 25: 1674-1679. doi: 10. 1101/gad. 16860911.
30. Huang H, Liu Y, Daniluk J, Gaiser S, Chu J, Wang H, Li ZS, Logsdon CD, Ji B. 2013. Activation of nuclear factorkappaB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology 144: 202-210. doi: 10. 1053/j. gastro. 2012. 09. 059.
31. Jensen JN, Cameron E, Garay MV, Starkey TW, Gianani R, Jensen J. 2005. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology 128: 728-741. doi: 10. 1053/j. gastro. 2004. 12. 008.
32. Ji B, Tsou L, Wang H, Gaiser S, Chang DZ, Daniluk J, Bi Y, Grote T, Longnecker DS, Logsdon CD. 2009. Ras activity levels control the development of pancreatic diseases. Gastroenterology 137: 1072-1082. 1082. e1-6. doi: 10. 1053/j. gastro. 2009. 05. 052.
33. Kawaguchi Y, Cooper B, GannonM, RayM, MacDonald RJ, Wright CV. 2002. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nature Genetics 32: 128-134. doi: 10. 1038/ng959.
34. Keefe MD, Wang H, De La O JP, Khan A, Firpo MA, Murtaugh LC. 2012. Beta-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice. Disease Models & Mechanisms 5: 503-514. doi: 10. 1242/dmm. 007799.
35. Khasawneh J, Schulz MD, Walch A, Rozman J, Hrabe de Angelis M, Klingenspor M, Buck A, Schwaiger M, Saur D, Schmid RM, Klöppel G, Sipos B, Greten FR, Arkan MC. 2009. Inflammation and mitochondrial fatty acid betaoxidation link obesity to early tumor promotion. Proceedings of the National Academy of Sciences of USA 106: 3354-3359. doi: 10. 1073/pnas. 0802864106.
36. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. 2013. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biology 14: R36. doi: 10. 1186/gb-2013-14-4-r36.
37. Kopinke D, Brailsford M, Pan FC, Magnuson MA, Wright CV, Murtaugh LC. 2012. Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. Developmental Biology 362: 57-64. doi: 10. 1016/j. ydbio. 2011. 11. 010.
38. Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, Morris JPt, Pan FC, Akiyama H, Wright CV, Jensen K, Hebrok M, Sander M. 2012. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22: 737-750. doi: 10. 1016/j. ccr. 2012. 10. 025.
39. Kramer A, Green J, Pollard J Jr, Tugendreich S. 2014. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30: 523-530. doi: 10. 1093/bioinformatics/btt703.
40. Krapp A, Knofler M, Ledermann B, Burki K, Berney C, Zoerkler N, Hagenbuchle O, Wellauer PK. 1998. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes & Development 12: 3752-3763. doi: 10. 1101/gad. 12. 23. 3752.
41. Kurup S, Bhonde RR. 2002. Analysis and optimization of nutritional set-up for murine pancreatic acinar cells. Journal of the Pancreas 3: 8-15.
42. Liou GY, Doppler H, Necela B, Krishna M, Crawford HC, Raimondo M, Storz P. 2013. Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs. The Journal of Cell Biology 202: 563-577. doi: 10. 1083/jcb. 201301001.
43. Liu J, Willet SG, Bankaitis ED, Xu Y, Wright CV, Gu G. 2013. Non-parallel recombination limits Cre-LoxP-based reporters as precise indicators of conditional genetic manipulation. Genesis 51: 436-442. doi: 10. 1002/dvg. 22384.
44. Loboda A, Nebozhyn M, Klinghoffer R, Frazier J, Chastain M, Arthur W, Roberts B, Zhang T, Chenard M, Haines B, Andersen J, Nagashima K, Paweletz C, Lynch B, Feldman I, Dai H, Huang P, Watters J. 2010. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Medical Genomics 3: 26. doi: 10. 1186/1755-8794-3-26.
45. MacDonald RJ, Swift GH, Przybyla AE, Chirgwin JM. 1987. Isolation of RNA using guanidinium salts. Methods Enzymol 152: 219-227.
46. Maier HJ, Wagner M, Schips TG, Salem HH, Baumann B, Wirth T. 2013. Requirement of NEMO/IKKgamma for effective expansion of KRAS-induced precancerous lesions in the pancreas. Oncogene 32: 2690-2695. doi: 10. 1038/onc. 2012. 272.
47. Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N, Nedospasov SA, Balkwill FR, Tuveson DA, Hagemann T. 2011. Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. The Journal of Clinical Investigation 121: 4685-4699. doi: 10. 1172/JCI45797.
48. Marino S, Vooijs M, van Der Gulden H, Jonkers J, Berns A. 2000. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes & Development 14: 994-1004.
49. Masui T, Long Q, Beres TM, Magnuson MA, MacDonald RJ. 2007. Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. Genes & Development 21: 2629-2643. doi: 10. 1101/gad. 1575207.
50. Masui T, Swift GH, Deering T, Shen C, Coats WS, Long Q, Elsasser HP, Magnuson MA, MacDonald RJ. 2010. Replacement of Rbpj with Rbpjl in the PTF1 complex controls the final maturation of pancreatic acinar cells. Gastroenterology 139: 270-280. doi: 10. 1053/j. gastro. 2010. 04. 003.
51. Masui T, Swift GH, Hale MA, Meredith DM, Johnson JE, Macdonald RJ. 2008. Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood. Molecular and Cellular Biology 28: 5458-5468. doi: 10. 1128/MCB. 00549-08.
52. McAllister F, Bailey JM, Alsina J, Nirschl CJ, Sharma R, Fan H, Rattigan Y, Roeser JC, Lankapalli RH, Zhang H, Jaffee EM, Drake CG, Housseau F, Maitra A, Kolls JK, Sears CL, Pardoll DM, Leach SD. 2014. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25: 621-637. doi: 10. 1016/j. ccr. 2014. 03. 014.
53. Means AL, Meszoely IM, Suzuki K, Miyamoto Y, Rustgi AK, Coffey RJ Jr, Wright CV, Stoffers DA, Leach SD. 2005. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132: 3767-3776. doi: 10. 1242/dev. 01925.
54. Murtaugh LC. 2014. Pathogenesis of pancreatic cancer: lessons from animal models. Toxicologic Pathology 42: 217-228. doi: 10. 1177/0192623313508250.
55. Murtaugh LC, Keefe MD. 2015. Regeneration and repair of the exocrine pancreas. Annual Review of Physiology 77: 229-249. doi: 10. 1146/annurev-physiol-021014-071727.
56. Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. 2012. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22: 318-330. doi: 10. 1016/j. ccr. 2012. 08. 001.
57. Neuschwander-Tetri BA, Bridle KR, Wells LD, Marcu M, Ramm GA. 2000. Repetitive acute pancreatic injury in the mouse induces procollagen alpha1(I) expression colocalized to pancreatic stellate cells. Laboratory Investigation 80: 143-150. doi: 10. 1038/labinvest. 3780018.
58. Pan FC, Bankaitis ED, Boyer D, Xu X, Van de Casteele M, Magnuson MA, Heimberg H, Wright CV. 2013. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injuryinduced facultative restoration. Development 140: 751-764. doi: 10. 1242/dev. 090159.
59. Pasca di Magliano M, Logsdon CD. 2013. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 144: 1220-1229. doi: 10. 1053/j. gastro. 2013. 01. 071.
60. Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ, Jacobs KB, Arslan AA, Buenode-Mesquita HB, Gallinger S, Gross M, Helzlsouer K, Holly EA, Jacobs EJ, Klein AP, LaCroix A, Li D, Mandelson MT, Olson SH, Risch HA, Zheng W, Albanes D, Bamlet WR, Berg CD, Boutron-Ruault MC, Buring JE, Bracci PM, Canzian F, Clipp S, Cotterchio M, de Andrade M, Duell EJ, Gaziano JM, Giovannucci EL, Goggins M, Hallmans G, Hankinson SE, Hassan M, Howard B, Hunter DJ, Hutchinson A, Jenab M, Kaaks R, Kooperberg C, Krogh V, Kurtz RC, Lynch SM, McWilliams RR, Mendelsohn JB, Michaud DS, Parikh H, Patel AV, Peeters PH, Rajkovic A, Riboli E, Rodriguez L, Seminara D, Shu XO, Thomas G, Tjønneland A, Tobias GS, Trichopoulos D, Van Den Eeden SK, Virtamo J, Wactawski-Wende J, Wang Z, Wolpin BM, Yu H, Yu K, Zeleniuch-Jacquotte A, Fraumeni JF Jr, Hoover RN, Hartge P, Chanock SJ. 2010. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22. 1, 1q32. 1 and 5p15. 33. Nature Genetics 42: 224-228. doi: 10. 1038/ng. 522.
61. Pin CL, Rukstalis JM, Johnson C, Konieczny SF. 2001. The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. The Journal of Cell Biology 155: 519-530. doi: 10. 1083/jcb. 200105060.
62. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. 2012. EMT and dissemination precede pancreatic tumor formation. Cell 148: 349-361. doi: 10. 1016/j. cell. 2011. 11. 025.
63. Robinson MD, McCarthy DJ, Smyth GK. 2010. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26: 139-140. doi: 10. 1093/bioinformatics/btp616.
64. Rooman I, Real FX. 2012. Pancreatic ductal adenocarcinoma and acinar cells: a matter of differentiation and development? Gut 61: 449-458. doi: 10. 1136/gut. 2010. 235804.
65. Rose SD, Swift GH, Peyton MJ, Hammer RE, MacDonald RJ. 2001. The role of PTF1-P48 in pancreatic acinar gene expression. The Journal of Biological Chemistry 276: 44018-44026. doi: 10. 1074/jbc. M106264200.
66. Ryan DP, Hong TS, Bardeesy N. 2014. Pancreatic adenocarcinoma. The New England Journal of Medicine 371: 1039-1049. doi: 10. 1056/NEJMra1404198.
67. Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, Gloyn AL, Edghill EL, Hattersley AT, Wellauer PK, Goodwin G, Houlston RS. 2004. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nature Genetics 36: 1301-1305. doi: 10. 1038/ng1475.
68. Sendler M, Dummer A, Weiss FU, Kruger B, Wartmann T, Scharffetter-Kochanek K, van Rooijen N, Malla SR, Aghdassi A, Halangk W, Lerch MM, Mayerle J. 2013. Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut 62: 430-439. doi: 10. 1136/gutjnl-2011-300771.
69. Serra RW, Fang M, Park SM, Hutchinson L, Green MR. 2014. A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype. eLife 3: e02313. doi: 10. 7554/eLife. 02313.
70. Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, Van Dyke T, Kozlov S, Martin P, Tseng TW, Dawson DW, Donahue TR, Masamune A, Shimosegawa T, Apte MV, Wilson JS, Ng B, Lau SL, Gunton JE, Wahl GM, Hunter T, Drebin JA, O'Dwyer PJ, Liddle C, Tuveson DA, Downes M, Evans RM. 2014. Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159: 80-93. doi: 10. 1016/j. cell. 2014. 08. 007.
71. Shi C, Klein AP, Goggins M, Maitra A, Canto M, Ali S, Schulick R, Palmisano E, Hruban RH. 2009a. Increased Prevalence of precursor lesions in familial pancreatic Cancer patients. Clinical Cancer Research 15: 7737-7743. doi: 10. 1158/1078-0432. CCR-09-0004.
72. Shi G, Zhu L, Sun Y, Bettencourt R, Damsz B, Hruban RH, Konieczny SF. 2009b. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 136: 1368-1378. doi: 10. 1053/j. gastro. 2008. 12. 066.
73. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, Settleman J. 2009. A gene expression signature associated with 'K-Ras addiction' reveals regulators of EMT and tumor cell survival. Cancer Cell 15: 489-500. doi: 10. 1016/j. ccr. 2009. 03. 022.
74. Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, Jessell TM, Costantini F. 2001. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Developmental Biology 1: 4. doi: 10. 1186/1471-213X-1-4.
75. Strobel O, Dor Y, Alsina J, Stirman A, Lauwers G, Trainor A, Castillo CF, Warshaw AL, Thayer SP. 2007. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 133: 1999-2009. doi: 10. 1053/j. gastro. 2007. 09. 009.
76. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. 2005. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of USA 102: 15545-15550. doi: 10. 1073/pnas. 0506580102.
77. Thomas S, Bonchev D. 2010. A survey of current software for network analysis in molecular biology. Human Genomics 4: 353-360. doi: 10. 1186/1479-7364-4-5-353.
78. von Figura G, Fukuda A, Roy N, Liku ME, Morris Iv JP, Kim GE, Russ HA, Firpo MA, Mulvihill SJ, Dawson DW, Ferrer J, Mueller WF, Busch A, Hertel KJ, Hebrok M. 2014a. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nature Cell Biology 16: 255-267. doi: 10. 1038/ncb2916.
79. von Figura G, Morris JPt, Wright CV, Hebrok M. 2014b. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut 63: 656-664. doi: 10. 1136/gutjnl-2012-304287.
80. Wajapeyee N, Malonia SK, Palakurthy RK, Green MR. 2013. Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors. Genes & Development 27: 2221-2226. doi: 10. 1101/gad. 227413. 113.
81. Weedon MN, Cebola I, Patch AM, Flanagan SE, De Franco E, Caswell R, Rodriguez-Segui SA, Shaw-Smith C, Cho CH, Lango Allen H, Houghton JA, Roth CL, Chen R, Hussain K, Marsh P, Vallier L, Murray A, International Pancreatic Agenesis Consortium, Ellard S, Ferrer J, Hattersley AT. 2014. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nature Genetics 46: 61-64. doi: 10. 1038/ng. 2826.
82. Westmoreland JJ, Drosos Y, Kelly J, Ye J, Means AL, Washington MK, Sosa-Pineda B. 2012. Dynamic distribution of claudin proteins in pancreatic epithelia undergoing morphogenesis or neoplastic transformation. Developmental Dynamics 241: 583-594. doi: 10. 1002/dvdy. 23740.
83. Wu CY, Carpenter ES, Takeuchi KK, Halbrook CJ, Peverley LV, Bien H, Hall JC, DelGiorno KE, Pal D, Song Y, Shi C, Lin RZ, Crawford HC. 2014. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology 147: 1405-1416. e7. doi: 10. 1053/j. gastro. 2014. 08. 032.
84. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA. 2010. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467: 1114-1117. doi: 10. 1038/nature09515.
85. Zhang W, Nandakumar N, Shi Y, Manzano M, Smith A, Graham G, Gupta S, Vietsch EE, Laughlin SZ, Wadhwa M, Chetram M, Joshi M, Wang F, Kallakury B, Toretsky J, Wellstein A, Yi C. 2014. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Science Signaling 7: ra42. doi: 10. 1126/scisignal. 2005049.