Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme–producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia, and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes, and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these proinflammatory and prodifferentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis, and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases.


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Literature Cited

  1. Steinberg WM. 1.  2006. Acute pancreatitis. See Ref. 121 1241–69
  2. Pan FC, Wright C. 2.  2011. Pancreas organogenesis: from bud to plexus to gland. Dev. Dyn. 240:530–65 [Google Scholar]
  3. Shih HP, Wang A, Sander M. 3.  2013. Pancreas organogenesis: from lineage determination to morphogenesis. Annu. Rev. Cell Dev. Biol. 29:81–105 [Google Scholar]
  4. Kretzschmar K, Watt FM. 4.  2012. Lineage tracing. Cell 148:33–45 [Google Scholar]
  5. Pan FC, Bankaitis ED, Boyer D, Xu X, Van de Casteele M. 5.  et al. 2013. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140:751–64 [Google Scholar]
  6. Masui T, Long Q, Beres TM, Magnuson MA, MacDonald RJ. 6.  2007. Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. Genes Dev. 21:2629–43 [Google Scholar]
  7. Kopp JL, Dubois CL, Schaffer AE, Hao E, Shih HP. 7.  et al. 2011. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138:653–65 [Google Scholar]
  8. Solar M, Cardalda C, Houbracken I, Martin M, Maestro MA. 8.  et al. 2009. Pancreatic exocrine duct cells give rise to insulin-producing β cells during embryogenesis but not after birth. Dev. Cell 17:849–60 [Google Scholar]
  9. Zhou Q, Law AC, Rajagopal J, Anderson WJ, Gray PA, Melton DA. 9.  2007. A multipotent progenitor domain guides pancreatic organogenesis. Dev. Cell 13:103–14 [Google Scholar]
  10. Kopinke D, Murtaugh LC. 10.  2010. Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas. BMC Dev. Biol. 10:38 [Google Scholar]
  11. Forsmark CE. 11.  2006. Chronic pancreatitis. See Ref. 121 1271–1308
  12. Greer JB, Whitcomb DC. 12.  2009. Inflammation and pancreatic cancer: an evidence-based review. Curr. Opin. Pharmacol. 9:411–18 [Google Scholar]
  13. Whitcomb DC. 13.  2013. Genetic risk factors for pancreatic disorders. Gastroenterology 144:1292–302 [Google Scholar]
  14. Dawra R, Sah RP, Dudeja V, Rishi L, Talukdar R. 14.  et al. 2011. Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. Gastroenterology 141:2210–17.e2 [Google Scholar]
  15. Singh VP, Chari ST. 15.  2005. Protease inhibitors in acute pancreatitis: lessons from the bench and failed clinical trials. Gastroenterology 128:2172–74 [Google Scholar]
  16. Logsdon CD, Ji B. 16.  2013. The role of protein synthesis and digestive enzymes in acinar cell injury. Nat. Rev. Gastroenterol. Hepatol. 10:362–70 [Google Scholar]
  17. Bockman DE. 17.  1997. Morphology of the exocrine pancreas related to pancreatitis. Microsc. Res. Tech. 37:509–19 [Google Scholar]
  18. Bockman DE, Boydston WR, Anderson MC. 18.  1982. Origin of tubular complexes in human chronic pancreatitis. Am. J. Surg. 144:243–49 [Google Scholar]
  19. Willemer S, Adler G. 19.  1989. Histochemical and ultrastructural characteristics of tubular complexes in human acute pancreatitis. Dig. Dis. Sci. 34:46–55 [Google Scholar]
  20. Ebert M, Yokoyama M, Ishiwata T, Friess H, Buchler MW. 20.  et al. 1999. Alteration of fibroblast growth factor and receptor expression after acute pancreatitis in humans. Pancreas 18:240–46 [Google Scholar]
  21. Zimmermann A, Gloor B, Kappeler A, Uhl W, Friess H, Buchler MW. 21.  2002. Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans. Gut 51:574–78 [Google Scholar]
  22. Lerch MM, Gorelick FS. 22.  2013. Models of acute and chronic pancreatitis. Gastroenterology 144:1180–93 [Google Scholar]
  23. Willemer S, Elsasser HP, Adler G. 23.  1992. Hormone-induced pancreatitis. Eur. Surg. Res. 24:Suppl. 129–39 [Google Scholar]
  24. Halangk W, Lerch MM, Brandt-Nedelev B, Roth W, Ruthenbuerger M. 24.  et al. 2000. Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J. Clin. Investig. 106:773–81 [Google Scholar]
  25. Hofbauer B, Saluja AK, Lerch MM, Bhagat L, Bhatia M. 25.  et al. 1998. Intra-acinar cell activation of trypsinogen during caerulein-induced pancreatitis in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 275:G352–62 [Google Scholar]
  26. Sah RP, Dawra RK, Saluja AK. 26.  2013. New insights into the pathogenesis of pancreatitis. Curr. Opin. Gastroenterol. 29:523–30 [Google Scholar]
  27. Jensen JN, Cameron E, Garay MV, Starkey TW, Gianani R, Jensen J. 27.  2005. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology 128:728–41 [Google Scholar]
  28. Morris JP IV, Cano DA, Sekine S, Wang SC, Hebrok M. 28.  2010. β-Catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Investig. 120:508–20 [Google Scholar]
  29. Zhong B, Zhou Q, Toivola DM, Tao GZ, Resurreccion EZ, Omary MB. 29.  2004. Organ-specific stress induces mouse pancreatic keratin overexpression in association with NF-κB activation. J. Cell Sci. 117:1709–19 [Google Scholar]
  30. De La O J-P, Murtaugh LC. 30.  2009. Notch and Kras in pancreatic cancer: at the crossroads of mutation, differentiation and signaling. Cell Cycle 8:1860–64 [Google Scholar]
  31. Fendrich V, Esni F, Garay MV, Feldmann G, Habbe N. 31.  et al. 2008. Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology 135:621–31 [Google Scholar]
  32. Neuschwander-Tetri BA, Bridle KR, Wells LD, Marcu M, Ramm GA. 32.  2000. Repetitive acute pancreatic injury in the mouse induces procollagen α1I expression colocalized to pancreatic stellate cells. Lab. Investig. 80:143–50 [Google Scholar]
  33. Walker NI. 33.  1987. Ultrastructure of the rat pancreas after experimental duct ligation. I. The role of apoptosis and intraepithelial macrophages in acinar cell deletion. Am. J. Pathol. 126:439–51 [Google Scholar]
  34. Banting FG. 34.  1925. Nobel lecture: diabetes and insulin http://www.nobelprize.org/nobel_prizes/medicine/laureates/1923/banting-lecture.html
  35. Lehv M, Fitzgerald PJ. 35.  1968. Pancreatic acinar cell regeneration. IV. Regeneration after resection. Am. J. Pathol. 53:513–35 [Google Scholar]
  36. Bonner-Weir S, Trent DF, Weir GC. 36.  1983. Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J. Clin. Investig. 71:1544–53 [Google Scholar]
  37. Watanabe H, Saito H, Rychahou PG, Uchida T, Evers BM. 37.  2005. Aging is associated with decreased pancreatic acinar cell regeneration and phosphatidylinositol 3-kinase/Akt activation. Gastroenterology 128:1391–404 [Google Scholar]
  38. Rankin MM, Kushner JA. 38.  2009. Adaptive β-cell proliferation is severely restricted with advanced age. Diabetes 58:1365–72 [Google Scholar]
  39. Berrocal T, Luque AA, Pinilla I, Lassaletta L. 39.  2005. Pancreatic regeneration after near-total pancreatec-tomy in children with nesidioblastosis. Pediatr. Radiol. 35:1066–70 [Google Scholar]
  40. Menge BA, Tannapfel A, Belyaev O, Drescher R, Muller C. 40.  et al. 2008. Partial pancreatectomy in adult humans does not provoke β-cell regeneration. Diabetes 57:142–49 [Google Scholar]
  41. Tsiotos GG, Barry MK, Johnson CD, Sarr MG. 41.  1999. Pancreas regeneration after resection: Does it occur in humans?. Pancreas 19:310–13 [Google Scholar]
  42. Dor Y, Brown J, Martinez OI, Melton DA. 42.  2004. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46 [Google Scholar]
  43. Nir T, Melton DA, Dor Y. 43.  2007. Recovery from diabetes in mice by β cell regeneration. J. Clin. Investig. 117:2553–61 [Google Scholar]
  44. Strobel O, Dor Y, Alsina J, Stirman A, Lauwers G. 44.  et al. 2007. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 133:1999–2009 [Google Scholar]
  45. Desai BM, Oliver-Krasinski J, De Leon DD, Farzad C, Hong N. 45.  et al. 2007. Preexisting pancreatic acinar cells contribute to acinar cell, but not islet β cell, regeneration. J. Clin. Investig. 117:971–77 [Google Scholar]
  46. Keefe MD, Wang H, De La O J-P, Khan A, Firpo MA, Murtaugh LC. 46.  2012. β-Catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice. Dis. Models Mech. 5:503–14 [Google Scholar]
  47. Thorel F, Nepote V, Avril I, Kohno K, Desgraz R. 47.  et al. 2010. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature 464:1149–54 [Google Scholar]
  48. Criscimanna A, Speicher JA, Houshmand G, Shiota C, Prasadan K. 48.  et al. 2011. Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology 141:1451–62e6 [Google Scholar]
  49. Frossard JL, Rubbia-Brandt L, Wallig MA, Benathan M, Ott T. 49.  et al. 2003. Severe acute pancreatitis and reduced acinar cell apoptosis in the exocrine pancreas of mice deficient for the Cx32 gene. Gastroenterology 124:481–93 [Google Scholar]
  50. Dimagno MJ, Lee SH, Hao Y, Zhou SY, McKenna BJ, Owyang C. 50.  2005. A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (−/−) mice. Gastroenterology 129:665–81 [Google Scholar]
  51. Cano DA, Sekine S, Hebrok M. 51.  2006. Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. Gastroenterology 131:1856–69 [Google Scholar]
  52. Crawford HC, Scoggins CR, Washington MK, Matrisian LM, Leach SD. 52.  2002. Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas. J. Clin. Investig. 109:1437–44 [Google Scholar]
  53. Magnuson MA, Osipovich AB. 53.  2013. Pancreas-specific Cre driver lines and considerations for their prudent use. Cell Metab. 18:9–20 [Google Scholar]
  54. Kopinke D, Brailsford M, Pan FC, Magnuson MA, Wright CV, Murtaugh LC. 54.  2012. Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. Dev. Biol. 362:57–64 [Google Scholar]
  55. Stanger BZ, Stiles B, Lauwers GY, Bardeesy N, Mendoza M. 55.  et al. 2005. Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell 8:185–95 [Google Scholar]
  56. Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L. 56.  et al. 2007. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11:291–302 [Google Scholar]
  57. Gukovsky I, Gukovskaya AS, Blinman TA, Zaninovic V, Pandol SJ. 57.  1998. Early NF-κB activation is associated with hormone-induced pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 275:G1402–14 [Google Scholar]
  58. Grady T, Liang P, Ernst SA, Logsdon CD. 58.  1997. Chemokine gene expression in rat pancreatic acinar cells is an early event associated with acute pancreatitis. Gastroenterology 113:1966–75 [Google Scholar]
  59. Gukovskaya AS, Gukovsky I, Zaninovic V, Song M, Sandoval D. 59.  et al. 1997. Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-α. Role in regulating cell death and pancreatitis. J. Clin. Investig. 100:1853–62 [Google Scholar]
  60. Omary MB, Lugea A, Lowe AW, Pandol SJ. 60.  2007. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J. Clin. Investig. 117:50–59 [Google Scholar]
  61. Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW. 61.  et al. 1998. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43:128–33 [Google Scholar]
  62. Landsman L, Nijagal A, Whitchurch TJ, Vanderlaan RL, Zimmer WE. 62.  et al. 2011. Pancreatic mesenchyme regulates epithelial organogenesis throughout development. PLOS Biol. 9:e1001143 [Google Scholar]
  63. Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X. 63.  et al. 2012. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143:1073–83.e22 [Google Scholar]
  64. Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu C-C. 64.  et al. 2014. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719–34 [Google Scholar]
  65. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF. 65.  et al. 2014. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735–47 [Google Scholar]
  66. Gukovsky I, Li N, Todoric J, Gukovskaya A, Karin M. 66.  2013. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 144:1199–209.e4 [Google Scholar]
  67. Zheng L, Xue J, Jaffee EM, Habtezion A. 67.  2013. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology 144:1230–40 [Google Scholar]
  68. Sendler M, Dummer A, Weiss FU, Kruger B, Wartmann T. 68.  et al. 2013. Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut 62:430–39 [Google Scholar]
  69. Treiber M, Neuhöfer P, Anetsberger E, Einwächter H, Lesina M. 69.  et al. 2011. Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse model of chronic pancreatitis. Gastroenterology 141:1473–85e7 [Google Scholar]
  70. Folias AE, Penaranda C, Su AL, Bluestone JA, Hebrok M. 70.  2014. Aberrant innate immune activation following tissue injury impairs pancreatic regeneration. PLOS ONE 9:e102125 [Google Scholar]
  71. Demols A, Le Moine O, Desalle F, Quertinmont E, Van Laethem JL, Deviere J. 71.  2000. CD4+ T cells play an important role in acute experimental pancreatitis in mice. Gastroenterology 118:582–90 [Google Scholar]
  72. Bedrosian AS, Nguyen AH, Hackman M, Connolly MK, Malhotra A. 72.  et al. 2011. Dendritic cells promote pancreatic viability in mice with acute pancreatitis. Gastroenterology 141:1915–26e14 [Google Scholar]
  73. Denham W, Yang J, Fink G, Denham D, Carter G. 73.  et al. 1997. Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis. Gastroenterology 113:1741–46 [Google Scholar]
  74. Liou GY, Doppler H, Necela B, Krishna M, Crawford HC. 74.  et al. 2013. Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs. J. Cell Biol. 202:563–77 [Google Scholar]
  75. Gukovsky I, Gukovskaya A. 75.  2013. Nuclear factor-κB in pancreatitis: jack-of-all-trades, but which one is more important?. Gastroenterology 144:26–29 [Google Scholar]
  76. Huang H, Liu Y, Daniluk J, Gaiser S, Chu J. 76.  et al. 2013. Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology 144:202–10 [Google Scholar]
  77. Algul H, Treiber M, Lesina M, Nakhai H, Saur D. 77.  et al. 2007. Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis. J. Clin. Investig. 117:1490–501 [Google Scholar]
  78. Neuhofer P, Liang S, Einwachter H, Schwerdtfeger C, Wartmann T. 78.  et al. 2013. Deletion of IκBα activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology 144:192–201 [Google Scholar]
  79. Zhang H, Neuhofer P, Song L, Rabe B, Lesina M. 79.  et al. 2013. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J. Clin. Investig. 123:1019–31 [Google Scholar]
  80. Cuzzocrea S, Mazzon E, Dugo L, Centorrino T, Ciccolo A. 80.  et al. 2002. Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerulein in mice. Cytokine 18:274–85 [Google Scholar]
  81. Chao KC, Chao KF, Chuang CC, Liu SH. 81.  2006. Blockade of interleukin 6 accelerates acinar cell apoptosis and attenuates experimental acute pancreatitis in vivo. Br. J. Surg. 93:332–38 [Google Scholar]
  82. Shigekawa M, Hikita H, Kodama T, Shimizu S, Li W. 82.  et al. 2012. Pancreatic STAT3 protects mice against caerulein-induced pancreatitis via PAP1 induction. Am. J. Pathol. 181:2105–13 [Google Scholar]
  83. Afelik S, Jensen J. 83.  2013. Notch signaling in the pancreas: patterning and cell fate specification. WIREs Dev. Biol. 2:531–44 [Google Scholar]
  84. Siveke JT, Lubeseder-Martellato C, Lee M, Mazur PK, Nakhai H. 84.  et al. 2008. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 134:544–55 [Google Scholar]
  85. Kornberg TB. 85.  2014. The contrasting roles of primary cilia and cytonemes in Hh signaling. Dev. Biol. 394:1–5 [Google Scholar]
  86. Gao T, Zhou D, Yang C, Singh T, Penzo-Mendez A. 86.  et al. 2013. Hippo signaling regulates differentiation and maintenance in the exocrine pancreas. Gastroenterology 144:1543–53.e1 [Google Scholar]
  87. George NM, Day CE, Boerner BP, Johnson RL, Sarvetnick NE. 87.  2012. Hippo signaling regulates pancreas development through inactivation of Yap. Mol. Cell. Biol. 32:5116–28 [Google Scholar]
  88. Blaine SA, Ray KC, Anunobi R, Gannon MA, Washington MK, Means AL. 88.  2010. Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling. Development 137:2289–96 [Google Scholar]
  89. Ardito CM, Gruner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N. 89.  et al. 2012. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22:304–17 [Google Scholar]
  90. Murtaugh LC, Law AC, Dor Y, Melton DA. 90.  2005. β-Catenin is essential for pancreatic acinar but not islet development. Development 132:4663–74 [Google Scholar]
  91. Wells JM, Esni F, Boivin GP, Aronow BJ, Stuart W. 91.  et al. 2007. Wnt/β-catenin signaling is required for development of the exocrine pancreas. BMC Dev. Biol. 7:4 [Google Scholar]
  92. Strom A, Bonal C, Ashery-Padan R, Hashimoto N, Campos ML. 92.  et al. 2007. Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas. Development 134:2719–25 [Google Scholar]
  93. Heiser PW, Lau J, Taketo MM, Herrera PL, Hebrok M. 93.  2006. Stabilization of β-catenin impacts pancreas growth. Development 133:2023–32 [Google Scholar]
  94. Valenta T, Hausmann G, Basler K. 94.  2012. The many faces and functions of β-catenin. EMBO J. 31:2714–36 [Google Scholar]
  95. Lin SL, Li B, Rao S, Yeo EJ, Hudson TE. 95.  et al. 2010. Macrophage Wnt7b is critical for kidney repair and regeneration. PNAS 107:4194–99 [Google Scholar]
  96. Hale MA, Swift GH, Hoang CQ, Deering TG, Masui T. 96.  et al. 2014. The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell-formation and acinar differentiation during pancreatic organogenesis. Development 141:3123–33 [Google Scholar]
  97. von Figura G, Morris JP IV, Wright CV, Hebrok M. 97.  2014. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut 63:656–64 [Google Scholar]
  98. Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL. 98.  et al. 2012. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22:737–50 [Google Scholar]
  99. Holmstrom SR, Deering T, Swift GH, Poelwijk FJ, Mangelsdorf DJ. 99.  et al. 2011. LRH-1 and PTF1-L coregulate an exocrine pancreas–specific transcriptional network for digestive function. Genes Dev. 25:1674–79 [Google Scholar]
  100. Pin CL, Rukstalis JM, Johnson C, Konieczny SF. 100.  2001. The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J. Cell Biol. 155:519–30 [Google Scholar]
  101. Kowalik AS, Johnson CL, Chadi SA, Weston JY, Fazio EN, Pin CL. 101.  2007. Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292:G1123–32 [Google Scholar]
  102. Fukuda A, Morris JP IV, Hebrok M. 102.  2012. Bmi1 is required for regeneration of the exocrine pancreas in mice. Gastroenterology 143:821–31e2 [Google Scholar]
  103. Clair J, Soydaner-Azeloglu R, Lee KE, Taylor L, Livanos A. 103. Mallen–St et al. 2012. EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev. 26:439–44 [Google Scholar]
  104. Sun L, Mathews LA, Cabarcas SM, Zhang X, Yang A. 104.  et al. 2013. Epigenetic regulation of SOX9 by the NF-κB signaling pathway in pancreatic cancer stem cells. Stem Cells 31:1454–66 [Google Scholar]
  105. Lee JM, Lee YK, Mamrosh JL, Busby SA, Griffin PR. 105.  et al. 2011. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature 474:506–10 [Google Scholar]
  106. Sinha S, Chen JK. 106.  2006. Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat. Chem. Biol. 2:29–30 [Google Scholar]
  107. Pagliuca FW, Melton DA. 107.  2013. How to make a functional β-cell. Development 140:2472–83 [Google Scholar]
  108. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. 108.  2008. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 455:627–32 [Google Scholar]
  109. Li W, Nakanishi M, Zumsteg A, Shear M, Wright C. 109.  et al. 2014. In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. eLife 3:e01846 [Google Scholar]
  110. Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P. 110.  et al. 2014. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional β cell mass in diabetic mice. Nat. Biotechnol. 32:76–83 [Google Scholar]
  111. De La O J-P, Emerson LL, Goodman JL, Froebe SC, Illum BE. 111.  et al. 2008. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. PNAS 105:18907–12 [Google Scholar]
  112. Murtaugh LC. 112.  2014. Pathogenesis of pancreatic cancer: lessons from animal models. Toxicol. Pathol. 42:217–28 [Google Scholar]
  113. Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. 113.  2012. EGF receptor signaling is essential for k-Ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22:318–30 [Google Scholar]
  114. Fukuda A, Wang SC, Morris JP IV, Folias AE, Liou A. 114.  et al. 2011. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19:441–55 [Google Scholar]
  115. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M. 115.  et al. 2011. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19:456–69 [Google Scholar]
  116. Daniluk J, Liu Y, Deng D, Chu J, Huang H. 116.  et al. 2012. An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J. Clin. Investig. 122:1519–28 [Google Scholar]
  117. Maier HJ, Wagner M, Schips TG, Salem HH, Baumann B, Wirth T. 117.  2012. Requirement of NEMO/IKKγ for effective expansion of KRAS-induced precancerous lesions in the pancreas. Oncogene 32:2690–95 [Google Scholar]
  118. Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N. 118.  et al. 2011. Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. J. Clin. Investig. 121:4685–99 [Google Scholar]
  119. Hanlon L, Avila JL, Demarest RM, Troutman S, Allen M. 119.  et al. 2010. Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res. 70:4280–86 [Google Scholar]
  120. Shi G, Zhu L, Sun Y, Bettencourt R, Damsz B. 120.  et al. 2009. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 136:1368–78 [Google Scholar]
  121. Sleisenger MH, Feldman M, Friedman LS, Brandt LJ. 121.  2006. Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management Philadelphia: Saunders

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