Skip to main content

Advertisement

SpringerLink
Log in

Molecular signaling in pancreatic ductal metaplasia: emerging biomarkers for detection and intervention of early pancreatic cancer

  • Review
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Pancreatic ductal metaplasia (PDM) is the transformation of potentially various types of cells in the pancreas into ductal or ductal-like cells, which eventually replace the existing differentiated somatic cell type(s). PDM is usually triggered by and manifests its ability to adapt to environmental stimuli and genetic insults. The development of PDM to atypical hyperplasia or dysplasia is an important risk factor for pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDA). Recent studies using genetically engineered mouse models, cell lineage tracing, single-cell sequencing and others have unraveled novel cellular and molecular insights in PDM formation and evolution. Those novel findings help better understand the cellular origins and functional significance of PDM and its regulation at cellular and molecular levels. Given that PDM represents the earliest pathological changes in PDA initiation and development, translational studies are beginning to define PDM-associated cell and molecular biomarkers that can be used to screen and detect early PDA and to enable its effective intervention, thereby truly and significantly reducing the dreadful mortality rate of PDA. This review will describe recent advances in the understanding of PDM biology with a focus on its underlying cellular and molecular mechanisms, and in biomarker discovery with clinical implications for the management of pancreatic regeneration and tumorigenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

All relevant data and material are availability for any inquiry.

Abbreviations

PDM:

pancreatic ductal metaplasia

ADM:

acinar-to-ductal metaplasia

CACs:

centroacinar cells

PDA:

pancreatic ductal adenocarcinoma

PanINs:

pancreatic intraepithelial neoplasias

MCNs:

mucinous cystic neoplasms

IPMNs:

intraductal papillary mucinous neoplasms

GEMMs:

genetically engineered mouse models

MPCs:

multipotent progenitor cells

TGF-α\β:

transforming growth factor-α\β

Ngn3:

Neurogenin 3

Hh:

Hedgehog

PDX-1:

pancreatic and duodenal homeobox 1

SOX9:

Sry-box protein 9

PTF1A:

pancreatic transcription factor 1 subunit alpha

AFLs:

atypical flat lesions

PDG:

pancreatic duct glands

PDL:

pancreatic duct ligation

bHLH:

basic helix-loop-helix

PKD1:

protein kinase D1

MPCs:

multipotent progenitor cells

Shh:

Sonic hedgehog

EGFR:

epidermal growth factor receptor

GRP78:

78-kDa glucose-regulated protein

FGF:

fibroblast growth factor

PYK2:

proline-rich tyrosine kinase 2

Sirt1:

NAD+-dependent protein deacetylase sirtuin-1

MAPK:

mitogen-activated protein kinase

Ptch1:

Patched1

Smo:

Smoothened

HDAC:

Histone deacetylase

YAP:

Yes-associated protein

BMP:

bone morphogenetic protein

IL:

interleukin

miRNA:

MicroRNA

CAII:

carbonic anhydrase II

COX-2:

Cyclooxygenase-2

MMP-7:

Matrix metalloproteinase-7

DCLK1:

Doublecortin-like kinase-1

HIF:

Hypoxia-inducible factor

ACVR1B:

Activin A receptor Ib

References

  1. J. Lardon, L. Bouwens, Metaplasia in the pancreas. Differentiation 73, 278–286 (2005)

    Article  CAS  PubMed  Google Scholar 

  2. D. Tosh, J.M. Slack, How cells change their phenotype. Nat. Rev. Mol. Cell. Biol. 3, 187–194 (2002)

    Article  CAS  PubMed  Google Scholar 

  3. A.R. Meyer, J.R. Goldenring, Injury, repair, inflammation and metaplasia in the stomach. J. Physiol. 596, 3861–3867 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. S.C. Shah, S. Gupta, D. Li, D. Morgan, R.A. Mustafa, A.J. Gawron, Spotlight: Gastric Intestinal Metaplasia. Gastroenterology 158, 704 (2020)

    Article  PubMed  Google Scholar 

  5. R.E. Leube, T.J. Rustad, Squamous cell metaplasia in the human lung: molecular characteristics of epithelial stratification. Virchows Arch. B Cell. Pathol. Incl. Mol. Pathol. 61, 227–253 (1991)

    Article  CAS  PubMed  Google Scholar 

  6. P. Correa, M.B. Piazuelo, K.T. Wilson, Pathology of gastric intestinal metaplasia: clinical implications. Am. J. Gastroenterol. 105, 493–498 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  7. V. Giroux, A.K. Rustgi, Metaplasia: tissue injury adaptation and a precursor to the dysplasia-cancer sequence. Nat. Rev. Cancer 17, 594–604 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. J.M. Slack, Metaplasia and transdifferentiation: from pure biology to the clinic. Nat. Rev. Mol. Cell. Biol. 8, 369–378 (2007)

    Article  CAS  PubMed  Google Scholar 

  9. P. Sharma, G.W. Falk, A.P. Weston, D. Reker, M. Johnston, R.E. Sampliner, Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clin. Gastroenterol. Hepatol. 4, 566–572 (2006)

    Article  PubMed  Google Scholar 

  10. J.M. Quinlan, B.J. Colleypriest, M. Farrant, D. Tosh, Epithelial metaplasia and the development of cancer. Biochim. Biophys. Acta 1776, 10–21 (2007)

    CAS  PubMed  Google Scholar 

  11. M.H. Cleveland, J.M. Sawyer, S. Afelik, J. Jensen, S.D. Leach, Exocrine ontogenies: on the development of pancreatic acinar, ductal and centroacinar cells. Semin Cell. Dev. Biol. 23, 711–719 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. F.C. Pan, C. Wright, Pancreas organogenesis: from bud to plexus to gland. Dev. Dyn. 240, 530–565 (2011)

    Article  CAS  PubMed  Google Scholar 

  13. S. Puri, M. Hebrok, Cellular plasticity within the pancreas–lessons learned from development. Dev. Cell. 18, 342–356 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. M. Reichert, A.K. Rustgi, Pancreatic ductal cells in development, regeneration, and neoplasia. J. Clin. Invest. 121, 4572–4578 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. J.M. Slack, Developmental biology of the pancreas. Development 121, 1569–1580 (1995)

    Article  CAS  PubMed  Google Scholar 

  16. A.A. Aughsteen, A comparative immunohistochemical study on amylase localization in the rat and human exocrine pancreas. Saudi Med. J. 22, 410–415 (2001)

    CAS  PubMed  Google Scholar 

  17. S.R. Hingorani, L. Wang, A.S. Multani, C. Combs, T.B. Deramaudt et al., Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005)

    Article  CAS  PubMed  Google Scholar 

  18. C. Guerra, A.J. Schuhmacher, M. Canamero, P.J. Grippo, L. Verdaguer et al., Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007)

    Article  CAS  PubMed  Google Scholar 

  19. P.J. Grippo, P.S. Nowlin, M.J. Demeure, D.S. Longnecker, E.P. Sandgren, Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res. 63, 2016–2019 (2003)

    CAS  PubMed  Google Scholar 

  20. I. Houbracken, E. de Waele, J. Lardon, Z. Ling, H. Heimberg et al., Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas. Gastroenterology 141, 731–741 (2011), 41 e1-4

    Article  PubMed  Google Scholar 

  21. S.R. Hingorani, E.F. Petricoin, A. Maitra, V. Rajapakse, C. King et al., Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003)

    Article  CAS  PubMed  Google Scholar 

  22. R.N. Wang, G. Kloppel, L. Bouwens, Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia 38, 1405–1411 (1995)

    Article  CAS  PubMed  Google Scholar 

  23. A.K. Saluja, V. Dudeja, Relevance of animal models of pancreatic cancer and pancreatitis to human disease. Gastroenterology 144, 1194–1198 (2013)

    Article  PubMed  Google Scholar 

  24. K. Hayashi, T. Takahashi, A. Kakita, S. Yamashina, Regional differences in the cellular proliferation activity of the regenerating rat pancreas after partial pancreatectomy. Arch. Histol. Cytol. 62, 337–346 (1999)

    Article  CAS  PubMed  Google Scholar 

  25. M. Wagner, H. Luhrs, G. Kloppel, G. Adler, R.M. Schmid, Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice. Gastroenterology 115, 1254–1262 (1998)

    Article  CAS  PubMed  Google Scholar 

  26. J. Liu, N. Akanuma, C. Liu, A. Naji, G.A. Halff et al., TGF-beta1 promotes acinar to ductal metaplasia of human pancreatic acinar cells. Sci. Rep. 6, 30904 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. B.Z. Stanger, M. Hebrok, Control of cell identity in pancreas development and regeneration. Gastroenterology 144, 1170–1179 (2013)

    Article  PubMed  Google Scholar 

  28. L.C. Murtaugh, M.D. Keefe, Regeneration and repair of the exocrine pancreas. Annu. Rev. Physiol. 77, 229–249 (2015)

    Article  CAS  PubMed  Google Scholar 

  29. L. Haeberle, I. Esposito, Pathology of pancreatic cancer. Transl. Gastroenterol. Hepatol. 4, 50 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  30. S. Crippa, C. Fernandez-Del Castillo, R. Salvia, D. Finkelstein, C. Bassi et al., Mucin-producing neoplasms of the pancreas: an analysis of distinguishing clinical and epidemiologic characteristics. Clin. Gastroenterol. Hepatol. 8, 213–219 (2010)

    Article  PubMed  Google Scholar 

  31. T.C. Cornish, R.H. Hruban, Pancreatic intraepithelial neoplasia. Surg. Pathol. Clin. 4, 523–535 (2011)

    Article  PubMed  Google Scholar 

  32. I. Parsa, D.S. Longnecker, D.G. Scarpelli, P. Pour, J.K. Reddy, M. Lefkowitz, Ductal metaplasia of human exocrine pancreas and its association with carcinoma. Cancer Res. 45, 1285–1290 (1985)

    CAS  PubMed  Google Scholar 

  33. K. Brune, T. Abe, M. Canto, L. O’Malley, A.P. Klein et al., Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am. J. Surg. Pathol. 30, 1067–1076 (2006)

    PubMed  PubMed Central  Google Scholar 

  34. G. Shi, D. DiRenzo, C. Qu, D. Barney, D. Miley, S.F. Konieczny, Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene 32, 1950–1958 (2013)

    Article  CAS  PubMed  Google Scholar 

  35. O. Strobel, Y. Dor, J. Alsina, A. Stirman, G. Lauwers et al., In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 133, 1999–2009 (2007)

    Article  PubMed  Google Scholar 

  36. M. Aichler, C. Seiler, M. Tost, J. Siveke, P.K. Mazur et al., Origin of pancreatic ductal adenocarcinoma from atypical flat lesions: a comparative study in transgenic mice and human tissues. J. Pathol. 226, 723–734 (2012)

    Article  CAS  PubMed  Google Scholar 

  37. A.J. Aguirre, N. Bardeesy, M. Sinha, L. Lopez, D.A. Tuveson et al., Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. N. Bardeesy, K.H. Cheng, J.H. Berger, G.C. Chu, J. Pahler et al., Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130–3146 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. L. Zhu, G. Shi, C.M. Schmidt, R.H. Hruban, S.F. Konieczny, Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Am. J. Pathol. 171, 263–273 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. D.A. Tuveson, L. Zhu, A. Gopinathan, N.A. Willis, L. Kachatrian et al., Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma. Cancer Res. 66, 242–247 (2006)

    Article  CAS  PubMed  Google Scholar 

  41. S. Kibe, K. Ohuchida, Y. Ando, S. Takesue, H. Nakayama et al., Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion. Cancer Lett. 444, 70–81 (2019)

    Article  CAS  PubMed  Google Scholar 

  42. J. Dissin, L.R. Mills, D.L. Mains, O. Black Jr., P.D. Webster III, Experimental induction of pancreatic adenocarcinoma in rats. J. Natl. Cancer Inst. 55, 857–864 (1975)

    Article  CAS  PubMed  Google Scholar 

  43. D.E. Bockman, O. Black Jr., L.R. Mills, P.D. Webster, Origin of tubular complexes developing during induction of pancreatic adenocarcinoma by 7,12-dimethylbenz(a)anthracene. Am. J. Pathol. 90, 645–658 (1978)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. B. Flaks, M.A. Moore, A. Flaks, Ultrastructural analysis of pancreatic carcinogenesis. III. Multifocal cystic lesions induced by N-nitroso-bis(2-hydroxypropyl)amine in the hamster exocrine pancreas. Carcinogenesis 1, 693–706 (1980)

    Article  CAS  PubMed  Google Scholar 

  45. M.H. Levitt, C.C. Harris, R. Squire, S. Springer, M. Wenk et al., Experimental pancreatic carcinogenesis. I. Morphogenesis of pancreatic adenocarcinoma in the Syrian golden hamster induced by N-nitroso-bis(2-hydroxypropyl)amine. Am. J. Pathol. 88, 5–28 (1977)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. R.L. Greer, B.K. Staley, A. Liou, M. Hebrok, Numb regulates acinar cell dedifferentiation and survival during pancreatic damage and acinar-to-ductal metaplasia. Gastroenterology 145, 1088–1097 e8 (2013)

    Article  CAS  PubMed  Google Scholar 

  47. D.E. Bockman, G. Merlino, Cytological changes in the pancreas of transgenic mice overexpressing transforming growth factor alpha. Gastroenterology 103, 1883–1892 (1992)

    Article  CAS  PubMed  Google Scholar 

  48. P. de la Porte Lechene, J. Iovanna, C. Odaira, R. Choux, H. Sarles, Z. Berger, Involvement of tubular complexes in pancreatic regeneration after acute necrohemorrhagic pancreatitis. Pancreas 6, 298–306 (1991)

    Article  Google Scholar 

  49. I. Esposito, C. Seiler, F. Bergmann, J. Kleeff, H. Friess, P. Schirmacher, Hypothetical progression model of pancreatic cancer with origin in the centroacinar-acinar compartment. Pancreas 35, 212–217 (2007)

    Article  PubMed  Google Scholar 

  50. C. Shi, A.P. Klein, M. Goggins, A. Maitra, M. Canto et al., Increased prevalence of precursor lesions in familial pancreatic cancer patients. Clin. Cancer Res. 15, 7737–7743 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. P.A. Perez-Mancera, C. Guerra, M. Barbacid, D.A. Tuveson, What we have learned about pancreatic cancer from mouse models. Gastroenterology 142, 1079–1092 (2012)

    Article  PubMed  Google Scholar 

  52. I. Rooman, F.X. Real, Pancreatic ductal adenocarcinoma and acinar cells: a matter of differentiation and development? Gut 61, 449–458 (2012)

    Article  PubMed  Google Scholar 

  53. E. Saponara, K. Grabliauskaite, M. Bombardo, R. Buzzi, A.B. Silva et al., Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas. J. Pathol. 237, 495–507 (2015)

    Article  CAS  PubMed  Google Scholar 

  54. N. Chuvin, D.F. Vincent, R.M. Pommier, L.B. Alcaraz, J. Gout et al., Acinar-to-ductal metaplasia induced by transforming growth factor beta facilitates KRAS(G12D)-driven pancreatic tumorigenesis. Cell. Mol. Gastroenterol. Hepatol. 4, 263–282 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  55. R.M.M. Ferreira, R. Sancho, H.A. Messal, E. Nye, B. Spencer-Dene et al., Duct- and acinar-derived pancreatic ductal adenocarcinomas show distinct tumor progression and marker expression. Cell. Rep. 21, 966–978 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. C. Shi, S.M. Hong, P. Lim, H. Kamiyama, M. Khan et al., KRAS2 mutations in human pancreatic acinar-ductal metaplastic lesions are limited to those with PanIN: implications for the human pancreatic cancer cell of origin. Mol. Cancer Res. 7, 230–236 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. N.T. van Heek, A.K. Meeker, S.E. Kern, C.J. Yeo, K.D. Lillemoe et al., Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am. J. Pathol. 161, 1541–1547 (2002)

    Article  PubMed  PubMed Central  Google Scholar 

  58. S.M. Hong, C.M. Heaphy, C. Shi, S.H. Eo, H. Cho et al., Telomeres are shortened in acinar-to-ductal metaplasia lesions associated with pancreatic intraepithelial neoplasia but not in isolated acinar-to-ductal metaplasias. Mod. Pathol. 24, 256–266 (2011)

    Article  PubMed  Google Scholar 

  59. N.I. Walker, C.M. Winterford, J.F. Kerr, Ultrastructure of the rat pancreas after experimental duct ligation. II. Duct and stromal cell proliferation, differentiation, and deletion. Pancreas 7, 420–434 (1992)

    Article  CAS  PubMed  Google Scholar 

  60. J.L. Iovanna, P. de la Porte Lechene, J.C. Dagorn, Expression of genes associated with dedifferentiation and cell proliferation during pancreatic regeneration following acute pancreatitis. Pancreas 7, 712–718 (1992)

    Article  CAS  PubMed  Google Scholar 

  61. S.Y. Song, M. Gannon, M.K. Washington, C.R. Scoggins, I.M. Meszoely et al., Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha. Gastroenterology 117, 1416–1426 (1999)

    Article  CAS  PubMed  Google Scholar 

  62. C. Paoli, A. Carrer, Organotypic culture of acinar cells for the study of pancreatic cancer initiation. Cancers (Basel) 12 (2020)

  63. D.E. Bockman, W.R. Boydston, M.C. Anderson, Origin of tubular complexes in human chronic pancreatitis. Am. J. Surg. 144, 243–249 (1982)

    Article  CAS  PubMed  Google Scholar 

  64. J.N. Jensen, E. Cameron, M.V. Garay, T.W. Starkey, R. Gianani, J. Jensen, Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology 128, 728–741 (2005)

    Article  CAS  PubMed  Google Scholar 

  65. A.L. Means, I.M. Meszoely, K. Suzuki, Y. Miyamoto, A.K. Rustgi et al., Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132, 3767–3776 (2005)

    Article  CAS  PubMed  Google Scholar 

  66. R.J. MacDonald, G.H. Swift, F.X. Real, Transcriptional control of acinar development and homeostasis. Prog Mol. Biol. Transl Sci. 97, 1–40 (2010)

    Article  CAS  PubMed  Google Scholar 

  67. J.M. Bailey, J. Alsina, Z.A. Rasheed, F.M. McAllister, Y.Y. Fu et al., DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 146, 245–256 (2014)

    Article  CAS  PubMed  Google Scholar 

  68. W. Qiu, H.E. Remotti, S.M. Tang, E. Wang, L. Dobberteen et al., Pancreatic DCLK1(+) cells originate distinctly from PDX1(+) progenitors and contribute to the initiation of intraductal papillary mucinous neoplasm in mice. Cancer Lett. 423, 71–79 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. B. Schutz, A.L. Ruppert, O. Strobel, M. Lazarus, Y. Urade et al., Distribution pattern and molecular signature of cholinergic tuft cells in human gastro-intestinal and pancreatic-biliary tract. Sci. Rep. 9, 17466 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  70. K.E. DelGiorno, R.F. Naeem, L. Fang, C.Y. Chung, C. Ramos et al., Tuft cell formation reflects epithelial plasticity in pancreatic injury: implications for modeling human pancreatitis. Front. Physiol. 11, 88 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  71. K.E. DelGiorno, C.Y. Chung, V. Vavinskaya, H.C. Maurer, S.W. Novak et al., Tuft Cells Inhibit Pancreatic Tumorigenesis in Mice by Producing Prostaglandin D2. Gastroenterology 159, 1866–1881 e8 (2020)

    Article  CAS  PubMed  Google Scholar 

  72. P. Storz, Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 14, 296–304 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Y. Schlesinger, O. Yosefov-Levi, D. Kolodkin-Gal, R.Z. Granit, L. Peters et al., Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity. Nat. Commun. 11, 4516 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. A.V. Pinho, I. Rooman, M. Reichert, N. De Medts, L. Bouwens et al., Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence programme that is present in chronic pancreatitis. Gut 60, 958–966 (2011)

    Article  CAS  PubMed  Google Scholar 

  75. Y. Miyamoto, A. Maitra, B. Ghosh, U. Zechner, P. Argani et al., Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3, 565–576 (2003)

    Article  CAS  PubMed  Google Scholar 

  76. P.P. Prevot, A. Simion, A. Grimont, M. Colletti, A. Khalaileh et al., Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut 61, 1723–1732 (2012)

    Article  CAS  PubMed  Google Scholar 

  77. M.A. Collins, W. Yan, J.S. Sebolt-Leopold, M. Pasca di Magliano, MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology 146, 822 – 34 e7 (2014)

  78. M.L. Babicky, M.M. Harper, J. Chakedis, A. Cazes, E.S. Mose et al., MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages. Oncogene 38, 5599–5611 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. H. Ying, P. Dey, W. Yao, A.C. Kimmelman, G.F. Draetta et al., Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 30, 355–385 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. T. Yoshida, D. Hanahan, Murine pancreatic ductal adenocarcinoma produced by in vitro transduction of polyoma middle T oncogene into the islets of Langerhans. Am. J. Pathol. 145, 671–684 (1994)

    CAS  PubMed  PubMed Central  Google Scholar 

  81. N.M. Krah, O.J. De La, G.H. Swift, C.Q. Hoang, S.G. Willet et al., The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. Elife 4 (2015)

  82. A.Y.L. Lee, C.L. Dubois, K. Sarai, S. Zarei, D.F. Schaeffer et al., Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma. Gut 68, 487–498 (2019)

    Article  CAS  PubMed  Google Scholar 

  83. C.L. Pin, J.F. Ryan, R. Mehmood, Acinar cell reprogramming: a clinically important target in pancreatic disease. Epigenomics 7, 267–281 (2015)

    Article  CAS  PubMed  Google Scholar 

  84. Y. Xu, J. Liu, M. Nipper, P. Wang, Ductal vs. acinar? Recent insights into identifying cell lineage of pancreatic ductal adenocarcinoma. Ann. Pancreat. Cancer 2 (2019)

  85. K. Satake, A. Hiura, A new model for pancreatitis. Pancreas 16, 284–288 (1998)

    Article  CAS  PubMed  Google Scholar 

  86. M. Bombardo, E. Saponara, E. Malagola, R. Chen, G.M. Seleznik et al., Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar-to-ductal metaplasia. Br. J. Pharmacol. 174, 3865–3880 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. X. Tao, Q. Chen, N. Li, H. Xiang, Y. Pan et al., Serotonin-RhoA/ROCK axis promotes acinar-to-ductal metaplasia in caerulein-induced chronic pancreatitis. Biomed. Pharmacother 125, 109999 (2020)

    Article  CAS  PubMed  Google Scholar 

  88. H. Archer, N. Jura, J. Keller, M. Jacobson, D. Bar-Sagi, A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology 131, 1844–1855 (2006)

    Article  CAS  PubMed  Google Scholar 

  89. E. Hegyi, M. Sahin-Toth, Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice. Gut 68, 301–312 (2019)

    Article  CAS  PubMed  Google Scholar 

  90. F. Gui, Y. Zhang, J. Wan, X. Zhan, Y. Yao et al., Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H. J. Clin. Invest. 130, 189–202 (2020)

    Article  CAS  PubMed  Google Scholar 

  91. N. Habbe, G. Shi, R.A. Meguid, V. Fendrich, F. Esni et al., Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl. Acad. Sci. U S A 105, 18913–18918 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. D.A. Morris JPt, Cano, S. Sekine, S.C. Wang, M. Hebrok, Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520 (2010)

    Article  CAS  Google Scholar 

  93. S.Y. Gidekel Friedlander, G.C. Chu, E.L. Snyder, N. Girnius, G. Dibelius et al., Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. G. Shi, L. Zhu, Y. Sun, R. Bettencourt, B. Damsz et al., Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 136, 1368–1378 (2009)

    Article  CAS  PubMed  Google Scholar 

  95. N. Bardeesy, A.J. Aguirre, G.C. Chu, K.H. Cheng, L.V. Lopez et al., Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc. Natl. Acad. Sci. U S A 103, 5947–5952 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. K. Kojima, S.M. Vickers, N.V. Adsay, N.C. Jhala, H.G. Kim et al., Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res. 67, 8121–8130 (2007)

    Article  CAS  PubMed  Google Scholar 

  97. L. Wang, D. Xie, D. Wei, Pancreatic acinar-to-ductal metaplasia and pancreatic cancer. Methods Mol. Biol. 1882, 299–308 (2019)

    Article  CAS  PubMed  Google Scholar 

  98. A.M. Jamal, M. Lipsett, R. Sladek, S. Laganiere, S. Hanley, L. Rosenberg, Morphogenetic plasticity of adult human pancreatic islets of Langerhans. Cell. Death Differ. 12, 702–712 (2005)

    Article  CAS  PubMed  Google Scholar 

  99. B.M. Schmied, G. Liu, H. Matsuzaki, A. Ulrich, S. Hernberg et al., Differentiation of islet cells in long-term culture. Pancreas 20, 337–347 (2000)

    Article  CAS  PubMed  Google Scholar 

  100. O. Ishikawa, H. Ohigashi, S. Imaoka, I. Nakai, M. Mitsuo et al., The role of pancreatic islets in experimental pancreatic carcinogenicity. Am. J. Pathol. 147, 1456–1464 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  101. V.T. Solovyan, J. Keski-Oja, Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-beta binding proteins and activation of TGF-beta. Cell. Death Differ. 12, 815–826 (2005)

    Article  CAS  PubMed  Google Scholar 

  102. S. Yuan, L. Rosenberg, S. Paraskevas, D. Agapitos, W.P. Duguid, Transdifferentiation of human islets to pancreatic ductal cells in collagen matrix culture. Differentiation 61, 67–75 (1996)

    Article  CAS  PubMed  Google Scholar 

  103. R. Wang, J. Li, L. Rosenberg, Factors mediating the transdifferentiation of islets of Langerhans to duct epithelial-like structures. J. Endocrinol. 171, 309–318 (2001)

    Article  CAS  PubMed  Google Scholar 

  104. A.M. Jamal, M. Lipsett, A. Hazrati, S. Paraskevas, D. Agapitos et al., Signals for death and differentiation: a two-step mechanism for in vitro transformation of adult islets of Langerhans to duct epithelial structures. Cell. Death Differ. 10, 987–996 (2003)

    Article  CAS  PubMed  Google Scholar 

  105. O. Strobel, Y. Dor, A. Stirman, A. Trainor, C. Fernandez-del Castillo et al., Beta cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo. Proc. Natl. Acad. Sci. U S A 104, 4419–4424 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. K.C. Ray, K.M. Bell, J. Yan, G. Gu, C.H. Chung et al., Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model. PLoS One 6, e16786 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. F.H. Brembeck, F.S. Schreiber, T.B. Deramaudt, L. Craig, B. Rhoades et al., The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. Cancer Res. 63, 2005–2009 (2003)

    CAS  PubMed  Google Scholar 

  108. J.M. Bailey, A.M. Hendley, K.J. Lafaro, M.A. Pruski, N.C. Jones et al., p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. Oncogene 35, 4282–4288 (2016)

    Article  CAS  PubMed  Google Scholar 

  109. J.L. Kopp, C.L. Dubois, A.E. Schaffer, E. Hao, H.P. Shih et al., Sox9 + ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138, 653–665 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. J. Qian, J. Niu, M. Li, P.J. Chiao, M.S. Tsao, In vitro modeling of human pancreatic duct epithelial cell transformation defines gene expression changes induced by K-ras oncogenic activation in pancreatic carcinogenesis. Cancer Res. 65, 5045–5053 (2005)

    Article  CAS  PubMed  Google Scholar 

  111. O. Strobel, D.E. Rosow, E.Y. Rakhlin, G.Y. Lauwers, A.G. Trainor et al., Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia. Gastroenterology 138, 1166–1177 (2010)

    Article  PubMed  Google Scholar 

  112. S.F. Boj, C.I. Hwang, L.A. Baker, I.I. Chio, D.D. Engle et al., Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015)

    Article  CAS  PubMed  Google Scholar 

  113. M. Rovira, S.G. Scott, A.S. Liss, J. Jensen, S.P. Thayer, S.D. Leach, Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc. Natl. Acad. Sci. U S A 107, 75–80 (2010)

    Article  CAS  PubMed  Google Scholar 

  114. R.L. Beer, M.J. Parsons, M. Rovira, Centroacinar cells: At the center of pancreas regeneration. Dev. Biol. 413, 8–15 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. P.M. Pour, Pancreatic centroacinar cells. The regulator of both exocrine and endocrine function. Int. J. Pancreatol. 15, 51–64 (1994)

    Article  CAS  PubMed  Google Scholar 

  116. P.M. Pour, Mechanism of pseudoductular (tubular) formation during pancreatic carcinogenesis in the hamster model. An electron-microscopic and immunohistochemical study. Am. J. Pathol. 130, 335–344 (1988)

    CAS  PubMed  PubMed Central  Google Scholar 

  117. D. Kopinke, M. Brailsford, F.C. Pan, M.A. Magnuson, C.V. Wright, L.C. Murtaugh, Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. Dev. Biol. 362, 57–64 (2012)

    Article  CAS  PubMed  Google Scholar 

  118. T. Gasslander, I. Ihse, S. Smeds, The importance of the centroacinar region in cerulein-induced mouse pancreatic growth. Scand. J. Gastroenterol. 27, 564–570 (1992)

    Article  CAS  PubMed  Google Scholar 

  119. F. Delaspre, R.L. Beer, M. Rovira, W. Huang, G. Wang et al., Centroacinar cells are progenitors that contribute to endocrine pancreas regeneration. Diabetes 64, 3499–3509 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. E. Mameishvili, I. Serafimidis, S. Iwaszkiewicz, M. Lesche, S. Reinhardt et al., Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras-induced pancreatic cancer. Proc. Natl. Acad. Sci. U S A 116, 20679–20688 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. B.Z. Stanger, B. Stiles, G.Y. Lauwers, N. Bardeesy, M. Mendoza et al., Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell. 8, 185–195 (2005)

    Article  CAS  PubMed  Google Scholar 

  122. H. Zulewski, E.J. Abraham, M.J. Gerlach, P.B. Daniel, W. Moritz et al., Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50, 521–533 (2001)

    Article  CAS  PubMed  Google Scholar 

  123. S.Y. Kim, S.H. Lee, B.M. Kim, E.H. Kim, B.H. Min et al., Activation of nestin-positive duct stem (NPDS) cells in pancreas upon neogenic motivation and possible cytodifferentiation into insulin-secreting cells from NPDS cells. Dev. Dyn. 230, 1–11 (2004)

    Article  CAS  PubMed  Google Scholar 

  124. L. Huang, A. Holtzinger, I. Jagan, M. BeGora, I. Lohse et al., Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21, 1364–1371 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. G. Lanzoni, V. Cardinale, G. Carpino, The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: A new reference frame for disease and regeneration. Hepatology 64, 277–286 (2016)

    Article  PubMed  Google Scholar 

  126. P.L. Herrera, Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127, 2317–2322 (2000)

    Article  CAS  PubMed  Google Scholar 

  127. T. Serizawa, K. Hamada, M. Akashi, Polymerization within a molecular-scale stereoregular template. Nature 429, 52–55 (2004)

    Article  CAS  PubMed  Google Scholar 

  128. Q. Zhou, A.C. Law, J. Rajagopal, W.J. Anderson, P.A. Gray, D.A. Melton, A multipotent progenitor domain guides pancreatic organogenesis. Dev. Cell 13, 103–114 (2007)

    Article  CAS  PubMed  Google Scholar 

  129. M. Solar, C. Cardalda, I. Houbracken, M. Martin, M.A. Maestro et al., Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev. Cell 17, 849–860 (2009)

    Article  CAS  PubMed  Google Scholar 

  130. W. Li, M. Nakanishi, A. Zumsteg, M. Shear, C. Wright et al., In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. Elife 3, e01846 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. M.A. Hale, H. Kagami, L. Shi, A.M. Holland, H.P. Elsasser et al., The homeodomain protein PDX1 is required at mid-pancreatic development for the formation of the exocrine pancreas. Dev. Biol. 286, 225–237 (2005)

    Article  CAS  PubMed  Google Scholar 

  132. A. Inada, C. Nienaber, H. Katsuta, Y. Fujitani, J. Levine et al., Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc. Natl. Acad. Sci. U S A 105, 19915–19919 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. A. Delacour, V. Nepote, A. Trumpp, P.L. Herrera, Nestin expression in pancreatic exocrine cell lineages. Mech. Dev. 121, 3–14 (2004)

    Article  CAS  PubMed  Google Scholar 

  134. F. Esni, D.A. Stoffers, T. Takeuchi, S.D. Leach, Origin of exocrine pancreatic cells from nestin-positive precursors in developing mouse pancreas. Mech. Dev. 121, 15–25 (2004)

    Article  CAS  PubMed  Google Scholar 

  135. C. Carriere, E.S. Seeley, T. Goetze, D.S. Longnecker, M. Korc, The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia. Proc. Natl. Acad. Sci. U S A 104, 4437–4442 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. C.B. Westphalen, Y. Takemoto, T. Tanaka, M. Macchini, Z. Jiang et al., Dclk1 defines quiescent pancreatic progenitors that promote injury-induced regeneration and tumorigenesis. Cell Stem Cell 18, 441–455 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Y. Dor, J. Brown, O.I. Martinez, D.A. Melton, Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004)

    Article  CAS  PubMed  Google Scholar 

  138. B.M. Desai, J. Oliver-Krasinski, D.D. De Leon, C. Farzad, N. Hong et al., Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration. J. Clin. Invest. 117, 971–977 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. S. Bonner-Weir, D.F. Trent, G.C. Weir, Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J. Clin. Invest. 71, 1544–1553 (1983)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. X. Xiao, Z. Chen, C. Shiota, K. Prasadan, P. Guo et al., No evidence for beta cell neogenesis in murine adult pancreas. J. Clin. Invest. 123, 2207–2217 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. M.M. Rankin, C.J. Wilbur, K. Rak, E.J. Shields, A. Granger, J.A. Kushner, beta-Cells are not generated in pancreatic duct ligation-induced injury in adult mice. Diabetes 62, 1634–1645 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. S.I. Tschen, S. Dhawan, T. Gurlo, A. Bhushan, Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice. Diabetes 58, 1312–1320 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. M.M. Rankin, J.A. Kushner, Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes 58, 1365–1372 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. R. Barnett, Type 1 diabetes. Lancet 391, 195 (2018)

    Article  PubMed  Google Scholar 

  145. S.A. Bartow, K. Mukai, J. Rosai, Pseudoneoplastic proliferation of endocrine cells in pancreatic fibrosis. Cancer 47, 2627–2633 (1981)

    Article  CAS  PubMed  Google Scholar 

  146. G. Kloppel, G. Bommer, G. Commandeur, P. Heitz, The endocrine pancreas in chronic pancreatitis. Immunocytochemical and ultrastructural studies. Virchows Arch. A Pathol. Anat. Histol. 377, 157–174 (1978)

    Article  CAS  PubMed  Google Scholar 

  147. X. Xu, J. D’Hoker, G. Stange, S. Bonne, N. De Leu et al., Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132, 197–207 (2008)

    Article  CAS  PubMed  Google Scholar 

  148. P.S. Misra, M.C. Nostro, Islet-resident endocrine progenitors: a new hope for beta cell PROCReation? Cell Stem Cell 26, 471–473 (2020)

    Article  CAS  PubMed  Google Scholar 

  149. A. Criscimanna, J.A. Speicher, G. Houshmand, C. Shiota, K. Prasadan et al., Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology 141, 1451–1462 (2011), 62 e1-6

    Article  CAS  PubMed  Google Scholar 

  150. J. Lardon, N. Huyens, I. Rooman, L. Bouwens, Exocrine cell transdifferentiation in dexamethasone-treated rat pancreas. Virchows Arch. 444, 61–65 (2004)

    Article  PubMed  Google Scholar 

  151. D. Gu, M. Arnush, N. Sarvetnick, Endocrine/exocrine intermediate cells in streptozotocin-treated Ins-IFN-gamma transgenic mice. Pancreas 15, 246–250 (1997)

    Article  CAS  PubMed  Google Scholar 

  152. F.C. Pan, E.D. Bankaitis, D. Boyer, X. Xu, M. Van de Casteele et al., Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140, 751–764 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. F. Thorel, V. Nepote, I. Avril, K. Kohno, R. Desgraz et al., Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149–1154 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. S. Chera, D. Baronnier, L. Ghila, V. Cigliola, J.N. Jensen et al., Diabetes recovery by age-dependent conversion of pancreatic delta-cells into insulin producers. Nature 514, 503–507 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. D. Gu, N. Sarvetnick, Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development 118, 33–46 (1993)

    Article  CAS  PubMed  Google Scholar 

  156. S.A. Blaine, K.C. Ray, R. Anunobi, M.A. Gannon, M.K. Washington, A.L. Means, Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling. Development 137, 2289–2296 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. L. Rosenberg, M. Lipsett, J.W. Yoon, M. Prentki, R. Wang et al., A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6J mice. Ann. Surg. 240, 875–884 (2004)

    Article  PubMed  PubMed Central  Google Scholar 

  158. S. Bonner-Weir, L.A. Baxter, G.T. Schuppin, F.E. Smith, A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 42, 1715–1720 (1993)

    Article  CAS  PubMed  Google Scholar 

  159. R.N. Wang, J.F. Rehfeld, F.C. Nielsen, G. Kloppel, Expression of gastrin and transforming growth factor-alpha during duct to islet cell differentiation in the pancreas of duct-ligated adult rats. Diabetologia 40, 887–893 (1997)

    Article  CAS  PubMed  Google Scholar 

  160. C. Bonal, F. Thorel, A. Ait-Lounis, W. Reith, A. Trumpp, P.L. Herrera, Pancreatic inactivation of c-Myc decreases acinar mass and transdifferentiates acinar cells into adipocytes in mice. Gastroenterology 136, 309 – 19 e9 (2009)

  161. V. Fendrich, F. Esni, M.V. Garay, G. Feldmann, N. Habbe et al., Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology 135, 621–631 (2008)

    Article  CAS  PubMed  Google Scholar 

  162. D.E. Bockman, Morphology of the exocrine pancreas related to pancreatitis. Microsc. Res. Tech. 37, 509–519 (1997)

    Article  CAS  PubMed  Google Scholar 

  163. M. Ebert, M. Yokoyama, T. Ishiwata, H. Friess, M.W. Buchler et al., Alteration of fibroblast growth factor and receptor expression after acute pancreatitis in humans. Pancreas 18, 240–246 (1999)

    Article  CAS  PubMed  Google Scholar 

  164. A. Zimmermann, B. Gloor, A. Kappeler, W. Uhl, H. Friess, M.W. Buchler, Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans. Gut 51, 574–578 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. A. Sharma, D.H. Zangen, P. Reitz, M. Taneja, M.E. Lissauer et al., The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes 48, 507–513 (1999)

    Article  CAS  PubMed  Google Scholar 

  166. A. Maitra, N. Fukushima, K. Takaori, R.H. Hruban, Precursors to invasive pancreatic cancer. Adv. Anat. Pathol. 12, 81–91 (2005)

    Article  PubMed  Google Scholar 

  167. O.J. De La, L.L. Emerson, J.L. Goodman, S.C. Froebe, B.E. Illum et al., Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc. Natl. Acad. Sci. U S A 105, 18907–18912 (2008)

    Article  Google Scholar 

  168. C. Guerra, M. Collado, C. Navas, A.J. Schuhmacher, I. Hernandez-Porras et al., Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. T. Furukawa, G. Kloppel, N. Volkan Adsay, J. Albores-Saavedra, N. Fukushima et al., Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Arch. 447, 794–799 (2005)

    Article  PubMed  Google Scholar 

  170. M. Kosmahl, U. Pauser, K. Peters, B. Sipos, J. Luttges et al., Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal. Virchows Arch. 445, 168–178 (2004)

    Article  CAS  PubMed  Google Scholar 

  171. R.H. Hruban, K. Takaori, D.S. Klimstra, N.V. Adsay, J. Albores-Saavedra et al., An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am. J. Surg. Pathol. 28, 977–987 (2004)

    Article  PubMed  Google Scholar 

  172. J. Yamaguchi, M. Mino-Kenudson, A.S. Liss, S. Chowdhury, T.C. Wang et al., Loss of trefoil factor 2 from pancreatic duct glands promotes formation of intraductal papillary mucinous neoplasms in mice. Gastroenterology 151, 1232-1244 e10 (2016)

    Article  CAS  PubMed  Google Scholar 

  173. G. von Figura, A. Fukuda, N. Roy, M.E. Liku, J.P. Morris Iv et al., The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat. Cell. Biol. 16, 255–267 (2014)

    Article  CAS  Google Scholar 

  174. S.C. Morris JPt, Wang, M. Hebrok, KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat. Rev. Cancer 10, 683–695 (2010)

    Article  CAS  Google Scholar 

  175. A. Inada, C. Nienaber, S. Fonseca, S. Bonner-Weir, Timing and expression pattern of carbonic anhydrase II in pancreas. Dev. Dyn. 235, 1571–1577 (2006)

    Article  CAS  PubMed  Google Scholar 

  176. B. Burghardt, M.L. Elkaer, T.H. Kwon, G.Z. Racz, G. Varga et al., Distribution of aquaporin water channels AQP1 and AQP5 in the ductal system of the human pancreas. Gut 52, 1008–1016 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. D. Kopinke, L.C. Murtaugh, Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas. BMC Dev. Biol. 10, 38 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. F. Zhang, D. Ma, T. Liu, Y.H. Liu, J. Guo et al., Expansion and maintenance of CD133-expressing pancreatic ductal epithelial cells by inhibition of TGF-beta signaling. Stem Cells Dev. 28, 1236–1252 (2019)

    Article  CAS  PubMed  Google Scholar 

  179. C.R. Scoggins, I.M. Meszoely, M. Wada, A.L. Means, L. Yang, S.D. Leach, p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G827–G836 (2000)

    Article  CAS  PubMed  Google Scholar 

  180. G. Kilic, J. Wang, B. Sosa-Pineda, Osteopontin is a novel marker of pancreatic ductal tissues and of undifferentiated pancreatic precursors in mice. Dev. Dyn. 235, 1659–1667 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. M.A. Collins, F. Bednar, Y. Zhang, J.C. Brisset, S. Galban et al., Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Invest. 122, 639–653 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. B. Schmied, G. Liu, M.P. Moyer, I.S. Hernberg, W. Sanger et al., Induction of adenocarcinoma from hamster pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro. Carcinogenesis 20, 317–324 (1999)

    Article  CAS  PubMed  Google Scholar 

  183. B.M. Schmied, A. Ulrich, H. Matsuzaki, X. Ding, C. Ricordi et al., Transdifferentiation of human islet cells in a long-term culture. Pancreas 23, 157–171 (2001)

    Article  CAS  PubMed  Google Scholar 

  184. M.T. Yip-Schneider, D.S. Barnard, S.D. Billings, L. Cheng, D.K. Heilman et al., Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 21, 139–146 (2000)

    Article  CAS  PubMed  Google Scholar 

  185. J.K. Colby, R.D. Klein, M.J. McArthur, C.J. Conti, K. Kiguchi et al., Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression. Neoplasia 10, 782–796 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. H.M. Schuller, G. Kabalka, G. Smith, A. Mereddy, M. Akula, M. Cekanova, Detection of overexpressed COX-2 in precancerous lesions of hamster pancreas and lungs by molecular imaging: implications for early diagnosis and prevention. Chem. Med. Chem. 1, 603–610 (2006)

    Article  CAS  PubMed  Google Scholar 

  187. H. Funahashi, M. Satake, D. Dawson, N.A. Huynh, H.A. Reber et al., Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res. 67, 7068–7071 (2007)

    Article  CAS  PubMed  Google Scholar 

  188. H.C. Crawford, C.R. Scoggins, M.K. Washington, L.M. Matrisian, S.D. Leach, Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas. J. Clin. Invest. 109, 1437–1444 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. J.K. Bray, O.A. Elgamal, J. Jiang, L.S. Wright, D.S. Sutaria et al., Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury. Cell. Death Dis. 11, 138 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. J. Wang, G. Kilic, M. Aydin, Z. Burke, G. Oliver, B. Sosa-Pineda, Prox1 activity controls pancreas morphogenesis and participates in the production of “secondary transition” pancreatic endocrine cells. Dev. Biol. 286, 182–194 (2005)

    Article  CAS  PubMed  Google Scholar 

  191. Y. Drosos, G. Neale, J. Ye, L. Paul, E. Kuliyev et al., Prox1-heterozygosis sensitizes the pancreas to oncogenic Kras-induced neoplastic transformation. Neoplasia 18, 172–184 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. C.M. Benitez, W.R. Goodyer, S.K. Kim, Deconstructing pancreas developmental biology. Cold Spring Harb. Perspect. Biol. 4 (2012)

  193. H.L. Larsen, A. Grapin-Botton, The molecular and morphogenetic basis of pancreas organogenesis. Semin Cell. Dev. Biol. 66, 51–68 (2017)

    Article  CAS  PubMed  Google Scholar 

  194. A. Apelqvist, H. Li, L. Sommer, P. Beatus, D.J. Anderson et al., Notch signalling controls pancreatic cell differentiation. Nature 400, 877–881 (1999)

    Article  CAS  PubMed  Google Scholar 

  195. J. Jensen, E.E. Pedersen, P. Galante, J. Hald, R.S. Heller et al., Control of endodermal endocrine development by Hes-1. Nat. Genet. 24, 36–44 (2000)

    Article  CAS  PubMed  Google Scholar 

  196. L.C. Murtaugh, B.Z. Stanger, K.M. Kwan, D.A. Melton, Notch signaling controls multiple steps of pancreatic differentiation. Proc. Natl. Acad. Sci. U S A 100, 14920–14925 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. J. Hald, J.P. Hjorth, M.S. German, O.D. Madsen, P. Serup, J. Jensen, Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development. Dev. Biol. 260, 426–437 (2003)

    Article  CAS  PubMed  Google Scholar 

  198. F. Esni, B. Ghosh, A.V. Biankin, J.W. Lin, M.A. Albert et al., Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 131, 4213–4224 (2004)

    Article  CAS  PubMed  Google Scholar 

  199. P.A. Seymour, C.A. Collin, A.R. Egeskov-Madsen, M.C. Jorgensen, H. Shimojo et al., Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors. Dev. Cell 52, 731–747 (2020). (e8)

    Article  CAS  PubMed  Google Scholar 

  200. E.T. Sawey, H.C. Crawford, Metalloproteinases and cell fate: Notch just ADAMs anymore. Cell Cycle 7, 566–569 (2008)

    Article  CAS  PubMed  Google Scholar 

  201. G.Y. Liou, H. Doppler, U.B. Braun, R. Panayiotou, M. Scotti Buzhardt et al., Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. Nat. Commun. 6, 6200 (2015)

    Article  PubMed  CAS  Google Scholar 

  202. F. Oswald, S. Liptay, G. Adler, R.M. Schmid, NF-kappaB2 is a putative target gene of activated Notch-1 via RBP-Jkappa. Mol. Cell. Biol. 18, 2077–2088 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. L.C. Murtaugh, The what, where, when and how of Wnt/beta-catenin signaling in pancreas development. Organogenesis 4, 81–86 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  204. K. Scheibner, M. Bakhti, A. Bastidas-Ponce, H. Lickert, Wnt signaling: implications in endoderm development and pancreas organogenesis. Curr. Opin. Cell. Biol. 61, 48–55 (2019)

    Article  CAS  PubMed  Google Scholar 

  205. N. Sharon, J. Vanderhooft, J. Straubhaar, J. Mueller, R. Chawla et al., Wnt signaling separates the progenitor and endocrine compartments during pancreas development. Cell. Rep. 27, 2281-2291 e5 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. J. Dessimoz, C. Bonnard, J. Huelsken, A. Grapin-Botton, Pancreas-specific deletion of beta-catenin reveals Wnt-dependent and Wnt-independent functions during development. Curr. Biol. 15, 1677–1683 (2005)

    Article  CAS  PubMed  Google Scholar 

  207. L.C. Murtaugh, A.C. Law, Y. Dor, D.A. Melton, Beta-catenin is essential for pancreatic acinar but not islet development. Development 132, 4663–4674 (2005)

    Article  CAS  PubMed  Google Scholar 

  208. J.M. Wells, F. Esni, G.P. Boivin, B.J. Aronow, W. Stuart et al., Wnt/beta-catenin signaling is required for development of the exocrine pancreas. BMC Dev. Biol. 7, 4 (2007)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. E. Wauters, V.J. Sanchez-Arevalo Lobo, A.V. Pinho, A. Mawson, D. Herranz et al., Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer. Cancer Res. 73, 2357–2367 (2013)

    Article  CAS  PubMed  Google Scholar 

  210. C. Gao, G. Chen, D.H. Zhang, J. Zhang, S.F. Kuan et al., PYK2 is involved in premalignant acinar cell reprogramming and pancreatic ductal adenocarcinoma maintenance by phosphorylating beta-catenin(Y654). Cell. Mol. Gastroenterol. Hepatol. 8, 561–578 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  211. M. Hebrok, S.K. Kim, D.A. Melton, Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 12, 1705–1713 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. S.K. Kim, D.A. Melton, Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc. Natl. Acad. Sci. U S A 95, 13036–13041 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. H. Kawahira, N.H. Ma, E.S. Tzanakakis, A.P. McMahon, P.T. Chuang, M. Hebrok, Combined activities of hedgehog signaling inhibitors regulate pancreas development. Development 130, 4871–4879 (2003)

    Article  CAS  PubMed  Google Scholar 

  214. J.K. Mfopou, L. Bouwens, Hedgehog signals in pancreatic differentiation from embryonic stem cells: revisiting the neglected. Differentiation 76, 107–117 (2008)

    Article  CAS  PubMed  Google Scholar 

  215. P.A. Seymour, K.K. Freude, M.N. Tran, E.E. Mayes, J. Jensen et al., SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc. Natl. Acad. Sci. U S A 104, 1865–1870 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. J.L. Kopp, G. von Figura, E. Mayes, F.F. Liu, C.L. Dubois et al., Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. P. Jeannot, C. Callot, R. Baer, N. Duquesnes, C. Guerra et al., Loss of p27Kip(1) promotes metaplasia in the pancreas via the regulation of Sox9 expression. Oncotarget 6, 35880–35892 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  218. C.H. Wong, Y.J. Li, Y.C. Chen, Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer. World J. Gastroenterol. 22, 7046–7057 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. E. Quilichini, M. Fabre, T. Dirami, A. Stedman, M. De Vas et al., Pancreatic ductal deletion of Hnf1b disrupts exocrine homeostasis, leads to pancreatitis, and facilitates tumorigenesis. Cell. Mol. Gastroenterol. Hepatol. 8, 487–511 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  220. K.K. Das, S. Heeg, J.R. Pitarresi, M. Reichert, B. Bakir et al., ETV5 regulates ductal morphogenesis with Sox9 and is critical for regeneration from pancreatitis. Dev. Dyn. 247, 854–866 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. V. Fendrich, F. Jendryschek, S. Beeck, M. Albers, M. Lauth et al., Genetic and pharmacologic abrogation of Snail1 inhibits acinar-to-ductal metaplasia in precursor lesions of pancreatic ductal adenocarcinoma and pancreatic injury. Oncogene 37, 1845–1856 (2018)

    Article  CAS  PubMed  Google Scholar 

  222. H. Zhou, Y. Qin, S. Ji, J. Ling, J. Fu et al., SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer. Oncogene 37, 912–923 (2018)

    Article  CAS  PubMed  Google Scholar 

  223. S. Beel, L. Kolloch, L.H. Apken, L. Jurgens, A. Bolle et al., kappaB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis. Nat. Commun. 11, 3409 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. H.P. Shih, J.L. Kopp, M. Sandhu, C.L. Dubois, P.A. Seymour et al., A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development 139, 2488–2499 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. E. Liang, Y. Lu, Y. Shi, Q. Zhou, F. Zhi, MYEOV increases HES1 expression and promotes pancreatic cancer progression by enhancing SOX9 transactivity. Oncogene 39, 6437–6450 (2020)

    Article  CAS  PubMed  Google Scholar 

  226. A. Rodolosse, E. Chalaux, T. Adell, H. Hagege, A. Skoudy, F.X. Real, PTF1alpha/p48 transcription factor couples proliferation and differentiation in the exocrine pancreas [corrected]. Gastroenterology 127, 937–949 (2004)

    Article  CAS  PubMed  Google Scholar 

  227. S. Benitz, I. Regel, T. Reinhard, A. Popp, I. Schaffer et al., Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells. Oncotarget 7, 11424–11433 (2016)

    Article  PubMed  Google Scholar 

  228. S. Afelik, X. Qu, E. Hasrouni, M.A. Bukys, T. Deering et al., Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells. Development 139, 1744–1753 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. F.C. Lynn, S.B. Smith, M.E. Wilson, K.Y. Yang, N. Nekrep, M.S. German, Sox9 coordinates a transcriptional network in pancreatic progenitor cells. Proc. Natl. Acad. Sci. U S A 104, 10500–10505 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. N. Thompson, E. Gesina, P. Scheinert, P. Bucher, A. Grapin-Botton, RNA profiling and chromatin immunoprecipitation-sequencing reveal that PTF1a stabilizes pancreas progenitor identity via the control of MNX1/HLXB9 and a network of other transcription factors. Mol. Cell. Biol. 32, 1189–1199 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. B.L. Jakubison, P.G. Schweickert, S.E. Moser, Y. Yang, H. Gao et al., Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment. Mol. Oncol. 12, 1104–1124 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. T. Miyatsuka, H. Kaneto, T. Shiraiwa, T.A. Matsuoka, K. Yamamoto et al., Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev. 20, 1435–1440 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. J.Y. Park, S.M. Hong, D.S. Klimstra, M.G. Goggins, A. Maitra, R.H. Hruban, Pdx1 expression in pancreatic precursor lesions and neoplasms. Appl. Immunohistochem. Mol. Morphol. 19, 444–449 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. K. Ganguly, S.R. Krishn, S. Rachagani, R. Jahan, A. Shah et al., Secretory mucin 5AC promotes neoplastic progression by augmenting KLF4-mediated pancreatic cancer cell stemness. Cancer Res. 81, 91–102 (2021)

    Article  CAS  PubMed  Google Scholar 

  235. H. Hui, R. Perfetti, Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. Eur. J. Endocrinol. 146, 129–141 (2002)

    Article  CAS  PubMed  Google Scholar 

  236. P. Jacquemin, S.M. Durviaux, J. Jensen, C. Godfraind, G. Gradwohl et al., Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3. Mol. Cell. Biol. 20, 4445–4454 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. P. Jacquemin, F.P. Lemaigre, G.G. Rousseau, The Onecut transcription factor HNF-6 (OC-1) is required for timely specification of the pancreas and acts upstream of Pdx-1 in the specification cascade. Dev. Biol. 258, 105–116 (2003)

    Article  CAS  PubMed  Google Scholar 

  238. Q. Zhou, J. Brown, A. Kanarek, J. Rajagopal, D.A. Melton, In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627–632 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. H.W. Clayton, A.B. Osipovich, J.S. Stancill, J.D. Schneider, P.G. Vianna et al., Pancreatic inflammation redirects acinar to beta cell reprogramming. Cell. Rep. 17, 2028–2041 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. C. Navas, I. Hernandez-Porras, A.J. Schuhmacher, M. Sibilia, C. Guerra, M. Barbacid, EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318–330 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. R. Baer, C. Cintas, M. Dufresne, S. Cassant-Sourdy, N. Schonhuber et al., Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110alpha. Genes Dev. 28, 2621–2635 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  242. Y. Yamanaka, H. Friess, M. Buchler, H.G. Beger, L.I. Gold, M. Korc, Synthesis and expression of transforming growth factor beta-1, beta-2, and beta-3 in the endocrine and exocrine pancreas. Diabetes 42, 746–756 (1993)

    Article  CAS  PubMed  Google Scholar 

  243. C.A. Crisera, M.I. Rose, P.R. Connelly, M. Li, K.L. Colen et al., The ontogeny of TGF-beta1, -beta2, -beta3, and TGF-beta receptor-II expression in the pancreas: implications for regulation of growth and differentiation. J. Pediatr. Surg. 34, 689 – 93; discussion 93 – 4 (1999)

  244. S.G. Rane, J.H. Lee, H.M. Lin, Transforming growth factor-beta pathway: role in pancreas development and pancreatic disease. Cytokine Growth Factor Rev 17, 107–119 (2006)

    Article  CAS  PubMed  Google Scholar 

  245. Y. Totsuka, M. Tabuchi, I. Kojima, Y. Eto, H. Shibai, E. Ogata, Stimulation of insulin secretion by transforming growth factor-beta. Biochem. Biophys. Res. Commun. 158, 1060–1065 (1989)

    Article  CAS  PubMed  Google Scholar 

  246. Y. Sayo, H. Hosokawa, H. Imachi, K. Murao, M. Sato et al., Transforming growth factor beta induction of insulin gene expression is mediated by pancreatic and duodenal homeobox gene-1 in rat insulinoma cells. Eur. J. Biochem. 267, 971–978 (2000)

    Article  CAS  PubMed  Google Scholar 

  247. J. Ahnfelt-Ronne, P. Ravassard, C. Pardanaud-Glavieux, R. Scharfmann, P. Serup, Mesenchymal bone morphogenetic protein signaling is required for normal pancreas development. Diabetes 59, 1948–1956 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. H. Hua, Y.Q. Zhang, S. Dabernat, M. Kritzik, D. Dietz et al., BMP4 regulates pancreatic progenitor cell expansion through Id2. J. Biol. Chem. 281, 13574–13580 (2006)

    Article  CAS  PubMed  Google Scholar 

  249. J. Goulley, U. Dahl, N. Baeza, Y. Mishina, H. Edlund, BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion. Cell. Metab. 5, 207–219 (2007)

    Article  CAS  PubMed  Google Scholar 

  250. Y. Cao, W. Yang, M.A. Tyler, X. Gao, C. Duan et al., Noggin attenuates cerulein-induced acute pancreatitis and impaired autophagy. Pancreas 42, 301–307 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Y. Cao, M. Drake, J. Davis, B. Yang, T.C. Ko, Opposing roles of BMP and TGF-beta signaling pathways in pancreatitis: mechanisms and therapeutic implication. Adv. Res. Gastroenterol. Hepatol. 13 (2019)

  252. Y. Nagashio, H. Ueno, M. Imamura, H. Asaumi, S. Watanabe et al., Inhibition of transforming growth factor beta decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice. Lab. Invest. 84, 1610–1618 (2004)

    Article  CAS  PubMed  Google Scholar 

  253. M.A. Shields, K. Ebine, V. Sahai, K. Kumar, K. Siddiqui et al., Snail cooperates with KrasG12D to promote pancreatic fibrosis. Mol. Cancer Res. 11, 1078–1087 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. K. Ebine, C.R. Chow, B.T. DeCant, H.Z. Hattaway, P.J. Grippo et al., Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia. Sci. Rep. 6, 29133 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. D.E. Levy, C.K. Lee, What does Stat3 do? J. Clin. Invest. 109, 1143–1148 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. N.M. Chandler, J.J. Canete, M.P. Callery, Increased expression of NF-kappa B subunits in human pancreatic cancer cells. J. Surg. Res. 118, 9–14 (2004)

    Article  CAS  PubMed  Google Scholar 

  257. I. Gukovsky, A.S. Gukovskaya, T.A. Blinman, V. Zaninovic, S.J. Pandol, Early NF-kappaB activation is associated with hormone-induced pancreatitis. Am. J. Physiol. 275, G1402–G1414 (1998)

    CAS  PubMed  Google Scholar 

  258. J. Ling, Y. Kang, R. Zhao, Q. Xia, D.F. Lee et al., KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 21, 105–120 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. L.K. Chan, M. Gerstenlauer, B. Konukiewitz, K. Steiger, W. Weichert et al., Epithelial NEMO/IKKgamma limits fibrosis and promotes regeneration during pancreatitis. Gut 66, 1995–2007 (2017)

    Article  CAS  PubMed  Google Scholar 

  260. G.Y. Liou, H. Doppler, B. Necela, M. Krishna, H.C. Crawford et al., Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs. J. Cell. Biol. 202, 563–577 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. A. Fukuda, S.C. Wang, A.E. Morris JPt, Folias, A. Liou et al., Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19, 441–455 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. R.B. Corcoran, G. Contino, V. Deshpande, A. Tzatsos, C. Conrad et al., STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 71, 5020–5029 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. R. Gruber, R. Panayiotou, E. Nye, B. Spencer-Dene, G. Stamp, A. Behrens, YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling. Gastroenterology 151, 526–539 (2016)

    Article  CAS  PubMed  Google Scholar 

  264. M. Perusina Lanfranca, Y. Zhang, A. Girgis, S. Kasselman, J. Lazarus et al., Interleukin 22 signaling regulates acinar cell plasticity to promote pancreatic tumor development in mice. Gastroenterology 158, 1417-1432 e11 (2020)

    Article  CAS  PubMed  Google Scholar 

  265. J. Reichrath, S. Reichrath, A snapshot of the molecular biology of notch signaling: challenges and promises. Adv. Exp. Med. Biol. 1227, 1–7 (2020)

    Article  CAS  PubMed  Google Scholar 

  266. M. Rubey, N.F. Chhabra, D. Gradinger, A. Sanz-Moreno, H. Lickert et al., DLL1- and DLL4-mediated notch signaling is essential for adult pancreatic islet homeostasis. Diabetes 69, 915–926 (2020)

    Article  CAS  PubMed  Google Scholar 

  267. J.T. Siveke, C. Lubeseder-Martellato, M. Lee, P.K. Mazur, H. Nakhai et al., Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 134, 544–555 (2008)

    Article  CAS  PubMed  Google Scholar 

  268. W.C. Chung, L. Challagundla, Y. Zhou, M. Li, A. Atfi, K. Xu, Loss of Jag1 cooperates with oncogenic Kras to induce pancreatic cystic neoplasms. Life Sci. Alliance 4 (2021)

  269. Y. Nishikawa, Y. Kodama, M. Shiokawa, T. Matsumori, S. Marui et al., Hes1 plays an essential role in Kras-driven pancreatic tumorigenesis. Oncogene 38, 4283–4296 (2019)

    Article  CAS  PubMed  Google Scholar 

  270. A. Hidalgo-Sastre, R.L. Brodylo, C. Lubeseder-Martellato, B. Sipos, K. Steiger et al., Hes1 controls exocrine cell plasticity and restricts development of pancreatic ductal adenocarcinoma in a mouse model. Am. J. Pathol. 186, 2934–2944 (2016)

    Article  CAS  PubMed  Google Scholar 

  271. C.L. Pin, J.M. Rukstalis, C. Johnson, S.F. Konieczny, The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J. Cell. Biol. 155, 519–530 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. E.T. Sawey, J.A. Johnson, H.C. Crawford, Matrix metalloproteinase 7 controls pancreatic acinar cell transdifferentiation by activating the Notch signaling pathway. Proc. Natl. Acad. Sci. U S A 104, 19327–19332 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. D.S. Lorberbaum, L. Sussel, A Notch in time: Spatiotemporal analysis of Notch signaling during pancreas development. Dev. Cell 52, 681–682 (2020)

    Article  CAS  PubMed  Google Scholar 

  274. S. Chiba, Notch signaling in stem cell systems. Stem Cells 24, 2437–2447 (2006)

    Article  CAS  PubMed  Google Scholar 

  275. X.Y. Li, W.J. Zhai, C.B. Teng, Notch Signaling in Pancreatic Development. Int. J. Mol. Sci. 17 (2015)

  276. P.W. Heiser, J. Lau, M.M. Taketo, P.L. Herrera, M. Hebrok, Stabilization of beta-catenin impacts pancreas growth. Development 133, 2023–2032 (2006)

    Article  CAS  PubMed  Google Scholar 

  277. M.D. Keefe, H. Wang, O.J. De La, A. Khan, M.A. Firpo, L.C. Murtaugh, beta-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice. Dis. Model. Mech. 5, 503–514 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  278. B.K. Baumgartner, G. Cash, H. Hansen, S. Ostler, L.C. Murtaugh, Distinct requirements for beta-catenin in pancreatic epithelial growth and patterning. Dev. Biol. 391, 89–98 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Y. Zhang, W. Morris JPt, Yan, H.K. Schofield, A. Gurney et al., Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res. 73, 4909–4922 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. P.W. Heiser, D.A. Cano, L. Landsman, G.E. Kim, J.G. Kench et al., Stabilization of beta-catenin induces pancreas tumor formation. Gastroenterology 135, 1288–1300 (2008)

    Article  CAS  PubMed  Google Scholar 

  281. A. Apelqvist, U. Ahlgren, H. Edlund, Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr. Biol. 7, 801–804 (1997)

    Article  CAS  PubMed  Google Scholar 

  282. S. Roy, T. Qiao, C. Wolff, P.W. Ingham, Hedgehog signaling pathway is essential for pancreas specification in the zebrafish embryo. Curr. Biol. 11, 1358–1363 (2001)

    Article  CAS  PubMed  Google Scholar 

  283. S.P. Thayer, M.P. di Magliano, P.W. Heiser, C.M. Nielsen, D.J. Roberts et al., Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. H. Kayed, J. Kleeff, T. Osman, S. Keleg, M.W. Buchler, H. Friess, Hedgehog signaling in the normal and diseased pancreas. Pancreas 32, 119–129 (2006)

    Article  CAS  PubMed  Google Scholar 

  285. D.A. Cano, M. Hebrok, Hedgehog spikes pancreas regeneration. Gastroenterology 135, 347–351 (2008)

    Article  CAS  PubMed  Google Scholar 

  286. F. Wu, Y. Zhang, B. Sun, A.P. McMahon, Y. Wang, Hedgehog signaling: from basic biology to cancer therapy. Cell. Chem. Biol. 24, 252–280 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. S. Lodh, E.A. O’Hare, N.A. Zaghloul, Primary cilia in pancreatic development and disease. Birth Defects Res. C. Embryo Today 102, 139–158 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. F.K. Bangs, P. Miller, E. O’Neill, Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse. Dis. Model Mech. 13 (2020)

  289. D.A. Cano, N.S. Murcia, G.J. Pazour, M. Hebrok, Orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization. Development 131, 3457–3467 (2004)

    Article  CAS  PubMed  Google Scholar 

  290. X. Liu, J.R. Pitarresi, M.C. Cuitino, R.D. Kladney, S.A. Woelke et al., Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia. Genes Dev. 30, 1943–1955 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. F. Bangs, K.V. Anderson, Primary cilia and mammalian hedgehog signaling. Cold Spring Harb. Perspect. Biol. 9 (2017)

  292. O. Lioubinski, M. Muller, M. Wegner, M. Sander, Expression of Sox transcription factors in the developing mouse pancreas. Dev. Dyn. 227, 402–408 (2003)

    Article  CAS  PubMed  Google Scholar 

  293. J.L. Gnerlich, X. Ding, C. Joyce, K. Turner, C.D. Johnson et al., Increased SOX9 expression in premalignant and malignant pancreatic neoplasms. Ann. Surg. Oncol. 26, 628–634 (2019)

    Article  PubMed  Google Scholar 

  294. A. Besson, S.F. Dowdy, J.M. Roberts, CDK inhibitors: cell cycle regulators and beyond. Dev. Cell 14, 159–169 (2008)

    Article  CAS  PubMed  Google Scholar 

  295. S. Diersch, P. Wenzel, M. Szameitat, P. Eser, M.C. Paul et al., Efemp1 and p27(Kip1) modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models. Oncotarget 4, 277–288 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  296. M. Reichert, S. Takano, J. von Burstin, S.B. Kim, J.S. Lee et al., The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. Genes Dev. 27, 288–300 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. A. Cano, M.A. Perez-Moreno, I. Rodrigo, A. Locascio, M.J. Blanco et al., The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell. Biol. 2, 76–83 (2000)

    Article  CAS  PubMed  Google Scholar 

  298. A. Grimont, A.V. Pinho, M.J. Cowley, C. Augereau, A. Mawson et al., SOX9 regulates ERBB signalling in pancreatic cancer development. Gut 64, 1790–1799 (2015)

    Article  CAS  PubMed  Google Scholar 

  299. J.S. Burlison, Q. Long, Y. Fujitani, C.V. Wright, M.A. Magnuson, Pdx-1 and Ptf1a concurrently determine fate specification of pancreatic multipotent progenitor cells. Dev. Biol. 316, 74–86 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. A. Krapp, M. Knofler, S. Frutiger, G.J. Hughes, O. Hagenbuchle, P.K. Wellauer, The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix protein. EMBO J. 15, 4317–4329 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. M. Jiang, A.C. Azevedo-Pouly, T.G. Deering, C.Q. Hoang, D. DiRenzo et al., MIST1 and PTF1 collaborate in feed-forward regulatory loops that maintain the pancreatic acinar phenotype in adult mice. Mol. Cell. Biol. 36, 2945–2955 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. T. Masui, Q. Long, T.M. Beres, M.A. Magnuson, R.J. MacDonald, Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. Genes Dev. 21, 2629–2643 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. S.D. Rose, G.H. Swift, M.J. Peyton, R.E. Hammer, R.J. MacDonald, The role of PTF1-P48 in pancreatic acinar gene expression. J. Biol. Chem. 276, 44018–44026 (2001)

    Article  CAS  PubMed  Google Scholar 

  304. T.M. Beres, T. Masui, G.H. Swift, L. Shi, R.M. Henke, R.J. MacDonald, PTF1 is an organ-specific and Notch-independent basic helix-loop-helix complex containing the mammalian Suppressor of Hairless (RBP-J) or its paralogue, RBP-L. Mol. Cell. Biol. 26, 117–130 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. A.E. Schaffer, K.K. Freude, S.B. Nelson, M. Sander, Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev. Cell 18, 1022–1029 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. T. Masui, G.H. Swift, M.A. Hale, D.M. Meredith, J.E. Johnson, R.J. Macdonald, Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood. Mol. Cell. Biol. 28, 5458–5468 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  307. P. Martinelli, M. Canamero, N. del Pozo, F. Madriles, A. Zapata, F.X. Real, Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice. Gut 62, 1481–1488 (2013)

    Article  CAS  PubMed  Google Scholar 

  308. P. Martinelli, F. Madriles, M. Canamero, E.C. Pau, N.D. Pozo et al., The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice. Gut 65, 476–486 (2016)

    Article  CAS  PubMed  Google Scholar 

  309. M.A. Hale, G.H. Swift, C.Q. Hoang, T.G. Deering, T. Masui et al., The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis. Development 141, 3123–3133 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. M. Flandez, J. Cendrowski, M. Canamero, A. Salas, N. del Pozo et al., Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRas(G12V)-driven pancreatic tumourigenesis. Gut 63, 647–655 (2014)

    Article  CAS  PubMed  Google Scholar 

  311. T. Miyatsuka, T.A. Matsuoka, T. Shiraiwa, T. Yamamoto, I. Kojima, H. Kaneto, Ptf1a and RBP-J cooperate in activating Pdx1 gene expression through binding to Area III. Biochem. Biophys. Res. Commun. 362, 905–909 (2007)

    Article  CAS  PubMed  Google Scholar 

  312. P.O. Wiebe, J.D. Kormish, V.T. Roper, Y. Fujitani, N.I. Alston et al., Ptf1a binds to and activates area III, a highly conserved region of the Pdx1 promoter that mediates early pancreas-wide Pdx1 expression. Mol. Cell. Biol. 27, 4093–4104 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  313. M.F. Offield, T.L. Jetton, P.A. Labosky, M. Ray, R.W. Stein et al., PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983–995 (1996)

    Article  CAS  PubMed  Google Scholar 

  314. S. Ashizawa, F.C. Brunicardi, X.P. Wang, PDX-1 and the pancreas. Pancreas 28, 109–120 (2004)

    Article  PubMed  Google Scholar 

  315. G. Zhou, J. Yu, A. Wang, S.H. Liu, J. Sinnett-Smith et al., Metformin restrains pancreatic duodenal homeobox-1 (PDX-1) function by inhibiting ERK signaling in pancreatic ductal adenocarcinoma. Curr. Mol. Med. 16, 83–90 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  316. S.H. Liu, S. Patel, M.C. Gingras, J. Nemunaitis, G. Zhou et al., PDX-1: demonstration of oncogenic properties in pancreatic cancer. Cancer 117, 723–733 (2011)

    Article  CAS  PubMed  Google Scholar 

  317. H. Hui, C. Wright, R. Perfetti, Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells. Diabetes 50, 785–796 (2001)

    Article  CAS  PubMed  Google Scholar 

  318. I. Rooman, Y. Heremans, H. Heimberg, L. Bouwens, Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro. Diabetologia 43, 907–914 (2000)

    Article  CAS  PubMed  Google Scholar 

  319. P.J. Miettinen, M. Huotari, T. Koivisto, J. Ustinov, J. Palgi et al., Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors. Development 127, 2617–2627 (2000)

    Article  CAS  PubMed  Google Scholar 

  320. P. Miettinen, P. Ormio, E. Hakonen, M. Banerjee, T. Otonkoski, EGF receptor in pancreatic beta-cell mass regulation. Biochem. Soc. Trans. 36, 280–285 (2008)

    Article  CAS  PubMed  Google Scholar 

  321. Z.M. Lof-Ohlin, P. Nyeng, M.E. Bechard, K. Hess, E. Bankaitis et al., Erratum: EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity. Nat. Cell. Biol. 19, 1442 (2017)

    Article  CAS  PubMed  Google Scholar 

  322. M. Korc, B. Chandrasekar, Y. Yamanaka, H. Friess, M. Buchier, H.G. Beger, Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J. Clin. Invest. 90, 1352–1360 (1992)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  323. M. Arnush, D. Gu, C. Baugh, S.P. Sawyer, B. Mroczkowski et al., Growth factors in the regenerating pancreas of gamma-interferon transgenic mice. Lab. Invest. 74, 985–990 (1996)

    CAS  PubMed  Google Scholar 

  324. M. Wagner, F.R. Greten, C.K. Weber, S. Koschnick, T. Mattfeldt et al., A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes Dev. 15, 286–293 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  325. A.L. Means, K.C. Ray, A.B. Singh, M.K. Washington, R.H. Whitehead et al., Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology 124, 1020–1036 (2003)

    Article  CAS  PubMed  Google Scholar 

  326. K. Tobita, H. Kijima, S. Dowaki, H. Kashiwagi, Y. Ohtani et al., Epidermal growth factor receptor expression in human pancreatic cancer: Significance for liver metastasis. Int. J. Mol. Med. 11, 305–309 (2003)

    CAS  PubMed  Google Scholar 

  327. C.M. Ardito, B.M. Gruner, K.K. Takeuchi, C. Lubeseder-Martellato, N. Teichmann et al., EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304–317 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  328. S.N. Payne, M.E. Maher, N.H. Tran, D.R. Van De Hey, T.M. Foley et al., PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors. Oncogenesis 4, e169 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  329. W. Zhang, N. Nandakumar, Y. Shi, M. Manzano, A. Smith et al., Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci. Signal. 7, ra42 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  330. N.M. Chen, G. Singh, A. Koenig, G.Y. Liou, P. Storz et al., NFATc1 links EGFR signaling to induction of Sox9 transcription and acinar-ductal transdifferentiation in the pancreas. Gastroenterology 148, 1024-1034 e9 (2015)

    Article  CAS  PubMed  Google Scholar 

  331. E. Hessmann, J.S. Zhang, N.M. Chen, M. Hasselluhn, G.Y. Liou et al., NFATc4 regulates Sox9 gene expression in acinar cell plasticity and pancreatic cancer initiation. Stem Cells Int. 2016, 5272498 (2016)

  332. N.M. Chen, A. Neesse, M.L. Dyck, B. Steuber, A.O. Koenig et al., Context-dependent epigenetic regulation of nuclear factor of activated T Cells 1 in pancreatic plasticity. Gastroenterology 152, 1507-1520 e15 (2017)

    Article  CAS  PubMed  Google Scholar 

  333. M.N. Garcia, D. Grasso, M.B. Lopez-Millan, T. Hamidi, C. Loncle et al., IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation. J. Clin. Invest. 124, 4709–4722 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  334. T. Gao, D. Zhou, C. Yang, T. Singh, A. Penzo-Mendez et al., Hippo signaling regulates differentiation and maintenance in the exocrine pancreas. Gastroenterology 144, 1543–1553 (2013), 53 e1

    Article  CAS  PubMed  Google Scholar 

  335. R. Fan, N.G. Kim, B.M. Gumbiner, Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1. Proc. Natl. Acad. Sci. U S A 110, 2569–2574 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  336. B.V. Reddy, K.D. Irvine, Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev. Cell 24, 459–471 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  337. J. Shen, D.P. Ha, G. Zhu, D.F. Rangel, A. Kobielak et al., GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras-driven pancreatic tumorigenesis in mice. Proc. Natl. Acad. Sci. U S A 114, E4020–E4029 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  338. J. Massague, TGFbeta signalling in context. Nat. Rev. Mol. Cell. Biol. 13, 616–630 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  339. V. Syed, TGF-beta Signaling in Cancer. J. Cell. Biochem. 117, 1279–1287 (2016)

    Article  CAS  PubMed  Google Scholar 

  340. S. Itoh, P. ten Dijke, Negative regulation of TGF-beta receptor/Smad signal transduction. Curr. Opin. Cell. Biol. 19, 176–184 (2007)

    Article  CAS  PubMed  Google Scholar 

  341. A. Weiss, L. Attisano, The TGFbeta superfamily signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 2, 47–63 (2013)

    Article  CAS  PubMed  Google Scholar 

  342. T. Huang, L. David, V. Mendoza, Y. Yang, M. Villarreal et al., TGF-beta signalling is mediated by two autonomously functioning TbetaRI:TbetaRII pairs. EMBO J. 30, 1263–1276 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  343. A. Hata, Y.G. Chen, TGF-beta signaling from receptors to Smads. Cold Spring Harb. Perspect. Biol. 8 (2016)

  344. F. Sanvito, P.L. Herrera, J. Huarte, A. Nichols, R. Montesano et al., TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development 120, 3451–3462 (1994)

    Article  CAS  PubMed  Google Scholar 

  345. E.P. Bottinger, J.L. Jakubczak, I.S. Roberts, M. Mumy, P. Hemmati et al., Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas. EMBO J. 16, 2621–2633 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  346. F. Miralles, P. Czernichow, R. Scharfmann, Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development 125, 1017–1024 (1998)

    Article  CAS  PubMed  Google Scholar 

  347. S.K. Kim, M. Hebrok, Intercellular signals regulating pancreas development and function. Genes Dev. 15, 111–127 (2001)

    Article  CAS  PubMed  Google Scholar 

  348. H. Friess, Z. Lu, A. Andren-Sandberg, P. Berberat, A. Zimmermann et al., Moderate activation of the apoptosis inhibitor bcl-xL worsens the prognosis in pancreatic cancer. Ann. Surg. 228, 780–787 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  349. S. Wildi, J. Kleeff, J. Mayerle, A. Zimmermann, E.P. Bottinger et al., Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations. Gut 56, 685–692 (2007)

    Article  CAS  PubMed  Google Scholar 

  350. E. Riesle, H. Friess, L. Zhao, M. Wagner, W. Uhl et al., Increased expression of transforming growth factor beta s after acute oedematous pancreatitis in rats suggests a role in pancreatic repair. Gut 40, 73–79 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  351. K.B. Hahm, Y.H. Im, C. Lee, W.T. Parks, Y.J. Bang et al., Loss of TGF-beta signaling contributes to autoimmune pancreatitis. J. Clin. Invest. 105, 1057–1065 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  352. K. Grabliauskaite, E. Saponara, T. Reding, M. Bombardo, G.M. Seleznik et al., Inactivation of TGFbeta receptor II signalling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis. J. Pathol. 238, 434–445 (2016)

    Article  CAS  PubMed  Google Scholar 

  353. S. Zhao, Y. Wang, L. Cao, M.M. Ouellette, J.W. Freeman, Expression of oncogenic K-ras and loss of Smad4 cooperate to induce the expression of EGFR and to promote invasion of immortalized human pancreas ductal cells. Int. J. Cancer 127, 2076–2087 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  354. J. He, X. Sun, K.Q. Qian, X. Liu, Z. Wang, Y. Chen, Protection of cerulein-induced pancreatic fibrosis by pancreas-specific expression of Smad7. Biochim. Biophys. Acta 1792, 56–60 (2009)

    Article  CAS  PubMed  Google Scholar 

  355. H. Friess, Y. Yamanaka, M. Buchler, M. Ebert, H.G. Beger et al., Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105, 1846–1856 (1993)

    Article  CAS  PubMed  Google Scholar 

  356. N. Akanuma, J. Liu, G.Y. Liou, X. Yin, K.R. Bejar et al., Paracrine secretion of transforming growth factor beta by ductal cells promotes acinar-to-ductal metaplasia in cultured human exocrine pancreas tissues. Pancreas 46, 1202–1207 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  357. R.E. Wilentz, G.H. Su, J.L. Dai, A.B. Sparks, P. Argani et al., Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am. J. Pathol. 156, 37–43 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  358. D.R. Principe, J.A. Doll, J. Bauer, B. Jung, H.G. Munshi et al., TGF-beta: duality of function between tumor prevention and carcinogenesis. J. Natl. Cancer Inst. 106, djt369 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  359. D. Padua, J. Massague, Roles of TGFbeta in metastasis. Cell. Res. 19, 89–102 (2009)

    Article  CAS  PubMed  Google Scholar 

  360. M. Pickup, S. Novitskiy, H.L. Moses, The roles of TGFbeta in the tumour microenvironment. Nat. Rev. Cancer 13, 788–799 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  361. W. Wang, J.L. Abbruzzese, D.B. Evans, L. Larry, K.R. Cleary, P.J. Chiao, The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin. Cancer Res. 5, 119–127 (1999)

    CAS  PubMed  Google Scholar 

  362. J. Daniluk, Y. Liu, D. Deng, J. Chu, H. Huang et al., An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J. Clin. Invest. 122, 1519–1528 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  363. S. Herzig, S. Hedrick, I. Morantte, S.H. Koo, F. Galimi, M. Montminy, CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma. Nature 426, 190–193 (2003)

    Article  CAS  PubMed  Google Scholar 

  364. E. Maniati, M. Bossard, N. Cook, J.B. Candido, N. Emami-Shahri et al., Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. J. Clin. Invest. 121, 4685–4699 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  365. H. Algul, M. Treiber, M. Lesina, H. Nakhai, D. Saur et al., Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis. J. Clin. Invest. 117, 1490–1501 (2007)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  366. H. Yamamoto, F. Itoh, S. Iku, Y. Adachi, H. Fukushima et al., Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression. J. Clin. Oncol. 19, 1118–1127 (2001)

    Article  CAS  PubMed  Google Scholar 

  367. S. Vlachos, A.K. Tsaroucha, G. Konstantoudakis, F. Papachristou, G. Trypsianis et al., Serum profiles of M30, M65 and interleukin-17 compared with C-reactive protein in patients with mild and severe acute pancreatitis. J. Hepatobiliary Pancreat. Sci. 21, 911–918 (2014)

    Article  PubMed  Google Scholar 

  368. R. Jia, M. Tang, L. Qiu, R. Sun, L. Cheng et al., Increased interleukin-23/17 axis and C-reactive protein are associated with severity of acute pancreatitis in patients. Pancreas 44, 321–325 (2015)

    Article  CAS  PubMed  Google Scholar 

  369. J. Ni, G. Hu, J. Xiong, J. Shen, J. Shen et al., Involvement of interleukin-17A in pancreatic damage in rat experimental acute necrotizing pancreatitis. Inflammation 36, 53–65 (2013)

    Article  CAS  PubMed  Google Scholar 

  370. F. McAllister, J.M. Bailey, J. Alsina, C.J. Nirschl, R. Sharma et al., Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25, 621–637 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  371. C. Loncle, L. Bonjoch, E. Folch-Puy, M.B. Lopez-Millan, S. Lac et al., IL17 functions through the novel REG3beta-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer. Cancer Res. 75, 4852–4862 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  372. J.G. Norman, G.W. Fink, C. Sexton, G. Carter, Transgenic animals demonstrate a role for the IL-1 receptor in regulating IL-1beta gene expression at steady-state and during the systemic stress induced by acute pancreatitis. J. Surg. Res. 63, 231–236 (1996)

    Article  CAS  PubMed  Google Scholar 

  373. F. Marrache, S.P. Tu, G. Bhagat, S. Pendyala, C.H. Osterreicher et al., Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis. Gastroenterology 135, 1277–1287 (2008)

    Article  CAS  PubMed  Google Scholar 

  374. J.M. Halbleib, W.J. Nelson, Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev. 20, 3199–3214 (2006)

    Article  CAS  PubMed  Google Scholar 

  375. J.D. Serrill, M. Sander, H.P. Shih, Pancreatic exocrine tissue architecture and integrity are maintained by E-cadherin during postnatal development. Sci. Rep. 8, 13451 (2018)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  376. Y. Kaneta, T. Sato, Y. Hikiba, M. Sugimori, S. Sue et al., Loss of pancreatic E-cadherin causes pancreatitis-like changes and contributes to carcinogenesis. Cell. Mol. Gastroenterol. Hepatol. 9, 105–119 (2020)

    Article  PubMed  Google Scholar 

  377. L. Chen, C. Ma, Y. Bian, C. Shao, T. Wang et al., Aberrant expression of STYK1 and E-cadherin confer a poor prognosis for pancreatic cancer patients. Oncotarget 8, 111333–111345 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  378. A. Aghdassi, M. Sendler, A. Guenther, J. Mayerle, C.O. Behn et al., Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. Gut 61, 439–448 (2012)

    Article  CAS  PubMed  Google Scholar 

  379. E. Bernstein, S.Y. Kim, M.A. Carmell, E.P. Murchison, H. Alcorn et al., Dicer is essential for mouse development. Nat. Genet. 35, 215–217 (2003)

    Article  CAS  PubMed  Google Scholar 

  380. K. Endo, H. Weng, N. Kito, Y. Fukushima, N. Iwai, MiR-216a and miR-216b as markers for acute phased pancreatic injury. Biomed. Res. 34, 179–188 (2013)

    Article  CAS  PubMed  Google Scholar 

  381. D.S. Sutaria, J. Jiang, A.C. Azevedo-Pouly, L. Wright, J.A. Bray et al., Knockout of acinar enriched microRNAs in Mice promote duct formation but not pancreatic cancer. Sci. Rep. 9, 11147 (2019)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  382. Y.J. Wang, F. McAllister, J.M. Bailey, S.G. Scott, A.M. Hendley et al., Dicer is required for maintenance of adult pancreatic acinar cell identity and plays a role in Kras-driven pancreatic neoplasia. PLoS One 9, e113127 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  383. R. Morris JPt, Greer, H.A. Russ, G. von Figura, G.E. Kim et al., Dicer regulates differentiation and viability during mouse pancreatic cancer initiation. PLoS One 9, e95486 (2014)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We also are grateful to the members of our laboratory for their critical reading of the manuscript and constructive thoughts.

Authors’ information: KX is a professor, JH is a senior scientist and XL is a senior postdoctoral fellow on cancer research.

Funding

The work was partly supported by the National Natural Science Foundation of China (#82072632) and the Guangzhou Municipality Bureau of Science and Technology, Guangzhou, China (#202102010033).

Author information

Authors and Affiliations

  1. Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, 510006, China

    Xiaojia Li & Keping Xie

  2. Department of Pathology, The South China University of Technology School of Medicine, Guangzhou, China

    Xiaojia Li & Keping Xie

  3. Institute of Digestive Diseases Research, The South China University of Technology School of Medicine, Guangzhou, China

    Jie He

Authors
  1. Xiaojia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keping Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KX, XL, and JH reviewed the literature for the article, and wrote, reviewed and/or edited the manuscript before its submission. All the authors contributed to manuscript revision and approved the submitted final version.

Corresponding author

Correspondence to Keping Xie.

Ethics declarations

Ethics approval and consent to participate

N/A.

Consent for publication

All authors directly participated in the planning, execution, and analysis the work presented and have read and approved the final version. All authors provided consent for the publication.

Conflict of interest

All authors declare no conflict of interest of any sort.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, X., He, J. & Xie, K. Molecular signaling in pancreatic ductal metaplasia: emerging biomarkers for detection and intervention of early pancreatic cancer. Cell Oncol. 45, 201–225 (2022). https://doi.org/10.1007/s13402-022-00664-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-022-00664-x

Keywords

Search

Navigation