Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

Nature Reviews Gastroenterology & Hepatology volume 14, pages 296–304 (2017)Cite this article

Subjects

Key Points

  • Adult pancreatic acinar cells show high plasticity that enables a change in their differentiation commitment

  • Acinar-to-ductal metaplasia (ADM) is a mechanism needed for regeneration after inflammation or injury

  • ADM is a result of epigenetic silencing of markers of acinar cell identity, activation of drivers of acinar cell dedifferentiation or loss of acinar cell organization

  • ADM is driven by intrinsic and extrinsic signalling

  • ADM in the presence of oncogenic KRAS signalling is irreversible and leads to a duct-like cell type that forms pancreatic intraepithelial neoplasia

Abstract

Acinar cells in the adult pancreas show high plasticity and can undergo transdifferentiation to a progenitor-like cell type with ductal characteristics. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. Data from animal models show that cells that undergo ADM in response to oncogenic signalling are precursors for pancreatic intraepithelial neoplasia lesions, which can further progress to pancreatic ductal adenocarcinoma (PDAC). As human pancreatic adenocarcinoma is often diagnosed at a stage of metastatic disease, understanding the processes that lead to its initiation is important for the discovery of markers for early detection, as well as options that enable an early intervention. Here, the critical determinants of acinar cell plasticity are discussed, in addition to the intracellular and extracellular signalling events that drive acinar cell metaplasia and their contribution to development of PDAC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Acinar cell plasticity and metaplasia to duct-like cells in the adult pancreas.
Figure 2: Inflammatory macrophage-driven signalling leading to acinar-to-ductal metaplasia.
Figure 3: KRAS-driven intrinsic signalling pathways leading to irreversible acinar-to-ductal metaplasia in mice.
Figure 4: Oncogenic KRAS and inflammation as drivers of acinar-to-ductal metaplasia and clonal expansion.

Similar content being viewed by others

References

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

    Article  PubMed  PubMed Central  Google Scholar 

  2. Pinho, A. V. 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 

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

    Article  PubMed  Google Scholar 

  4. Liou, G. Y. 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 

  5. Logsdon, C. D. & Ji, B. Ras activity in acinar cells links chronic pancreatitis and pancreatic cancer. Clin. Gastroenterol. Hepatol. 7, S40–S43 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liou, G. Y. et al. Mutant KRas-induced mitochondrial oxidative stress in acinar cells upregulates EGFR signaling to drive formation of pancreatic precancerous lesions. Cell Rep. 14, 2325–2336 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hezel, A. F. et al. Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms. Mol. Cell. Biol. 28, 2414–2425 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sandgren, E. P., Luetteke, N. C., Palmiter, R. D., Brinster, R. L. & Lee, D. C. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 61, 1121–1135 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Liou, G. Y. et al. Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. Nat. Commun. 6, 6200 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Means, A. L. 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 

  11. Shi, G. et al. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene 32, 1950–1958 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Liu, J. 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 

  13. Houbracken, I. et al. Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas. Gastroenterology 141, 731–741.e4 (2011).

    Article  PubMed  Google Scholar 

  14. Kopp, J. L. 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). Using lineage tracing of pancreatic cell populations, the authors show that ductal and centroacinar cells are refractory to transformation by oncogenic KRAS, whereas acinar cells undergo metaplasia to a duct-like state and form precursors for PDAC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ardito, C. M. et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304–317 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ji, B. et al. Ras activity levels control the development of pancreatic diseases. Gastroenterology 137, 1072–1082.e6 (2009). Part of a series of papers from the Logsdon laboratory showing that acquisition of an oncogenic form of KRAS alone is not sufficient to drive development of PDAC. To progress to PDAC, the activities of wild-type and mutant KRAS need to be further increased.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Navas, C. et al. 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 

  18. Guerra, C. 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 

  19. Guerra, C. 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 

  20. Liou, G. Y. et al. Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov. 5, 52–63 (2015). The authors show that acquisition of an oncogenic KRAS mutation in acinar cells can induce the expression of chemoattractants for inflammatory macrophages, which then contribute to the ADM process.

    Article  CAS  PubMed  Google Scholar 

  21. Bardeesy, N. & DePinho, R. A. Pancreatic cancer biology and genetics. Nat. Rev. Cancer 2, 897–909 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Aichler, M. 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 

  23. Wagner, M., Luhrs, H., Kloppel, G., Adler, G. & Schmid, R. M. 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 

  24. Rodolosse, A. et al. PTF1alpha/p48 transcription factor couples proliferation and differentiation in the exocrine pancreas [corrected]. Gastroenterology 127, 937–949 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Masui, T. et al. Replacement of Rbpj with Rbpjl in the PTF1 complex controls the final maturation of pancreatic acinar cells. Gastroenterology 139, 270–280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Campos, M. L. et al. ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours. Biochem. J. 451, 395–405 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Benitz, S. 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 

  28. Krah, N. M. et al. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. eLife 4, e07125 (2015).

    Article  PubMed Central  Google Scholar 

  29. Pin, C. L., Rukstalis, J. M., Johnson, C. & Konieczny, S. F. 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 

  30. Direnzo, D. et al. Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells. Gastroenterology 143, 469–480 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Johnson, C. L. et al. Activation of protein kinase Cδ leads to increased pancreatic acinar cell dedifferentiation in the absence of MIST1. J. Pathol. 228, 351–365 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Shi, G. et al. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 136, 1368–1378 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhu, L. et al. Inhibition of Mist1 homodimer formation induces pancreatic acinar-to-ductal metaplasia. Mol. Cell. Biol. 24, 2673–2681 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jia, D., Sun, Y. & Konieczny, S. F. Mist1 regulates pancreatic acinar cell proliferation through p21 CIP1/WAF1. Gastroenterology 135, 1687–1697 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Grabliauskaite, K. et al. p21(WAF1) (/Cip1) limits senescence and acinar-to-ductal metaplasia formation during pancreatitis. J. Pathol. 235, 502–514 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Martinelli, P. et al. The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice. Gut 65, 476–486 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Hermann, P. C. et al. Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice. Gastroenterology 147, 1119–1133 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Kim, S. et al. The basic helix-loop-helix transcription factor E47 reprograms human pancreatic cancer cells to a quiescent acinar state with reduced tumorigenic potential. Pancreas 44, 718–727 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dey, P., Rachagani, S., Vaz, A. P., Ponnusamy, M. P. & Batra, S. K. PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia. Oncotarget 5, 4480–4491 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  40. von Figura, G., Morris, J. P. IV, Wright, C. V. & Hebrok, M. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut 63, 656–664 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Wang, Y. J. 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  CAS  PubMed  PubMed Central  Google Scholar 

  42. Flandez, M. 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 

  43. Morris, J. P. IV et al. Dicer regulates differentiation and viability during mouse pancreatic cancer initiation. PLoS ONE 9, e95486 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lu, C. D. et al. Loss of p27Kip1 expression independently predicts poor prognosis for patients with resectable pancreatic adenocarcinoma. Cancer 85, 1250–1260 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Jeannot, P. 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 

  46. Kopp, J. L. 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 

  47. Furuyama, K. et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat. Genet. 43, 34–41 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Prevot, P. P. 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  PubMed Central  Google Scholar 

  49. Shroff, S. et al. SOX9: a useful marker for pancreatic ductal lineage of pancreatic neoplasms. Hum. Pathol. 45, 456–463 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Grimont, A. et al. SOX9 regulates ERBB signalling in pancreatic cancer development. Gut 64, 1790–1799 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Chen, N. M. 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  PubMed Central  Google Scholar 

  52. Hessmann, E. et al. NFATc4 regulates Sox9 gene expression in acinar cell plasticity and pancreatic cancer initiation. Stem Cells Int. 2016, 5272498 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Park, J. Y. et al. Pdx1 expression in pancreatic precursor lesions and neoplasms. Appl. Immunohistochem. Mol. Morphol. 19, 444–449 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. Gu, G., Dubauskaite, J. & Melton, D. A. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, 2447–2457 (2002).

    CAS  PubMed  Google Scholar 

  56. Wescott, M. P. et al. Pancreatic ductal morphogenesis and the Pdx1 homeodomain transcription factor. Mol. Biol. Cell 20, 4838–4844 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Marty-Santos, L. & Cleaver, O. Pdx1 regulates pancreas tubulogenesis and E-cadherin expression. Development 143, 101–112 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Oliver-Krasinski, J. M. et al. The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice. J. Clin. Invest. 119, 1888–1898 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hale, M. A. 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 

  60. Miyatsuka, T. 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 

  61. Corcoran, R. B. 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 

  62. Gruber, R. et al. 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  PubMed Central  Google Scholar 

  63. Zhang, W. 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  CAS  PubMed  PubMed Central  Google Scholar 

  64. De La, O. J. et al. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc. Natl Acad. Sci. USA 105, 18907–18912 (2008).

    Article  Google Scholar 

  65. Esni, F. 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 

  66. Hald, J. et al. Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development. Dev. Biol. 260, 426–437 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Avila, J. L., Troutman, S., Durham, A. & Kissil, J. L. Notch1 is not required for acinar-to-ductal metaplasia in a model of Kras-induced pancreatic ductal adenocarcinoma. PLoS ONE 7, e52133 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hosokawa, S. et al. Impact of Sox9 dosage and Hes1-mediated Notch signaling in controlling the plasticity of adult pancreatic duct cells in mice. Sci. Rep. 5, 8518 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Delous, M. et al. Sox9b is a key regulator of pancreaticobiliary ductal system development. PLoS Genet. 8, e1002754 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Grippo, P. J. & Sandgren, E. P. Acinar-to-ductal metaplasia accompanies c-myc-induced exocrine pancreatic cancer progression in transgenic rodents. Int. J. Cancer 131, 1243–1248 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Wei, D. et al. KLF4 is essential for induction of cellular identity change and acinar-to-ductal reprogramming during early pancreatic carcinogenesis. Cancer Cell 29, 324–338 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hall, P. A. & Lemoine, N. R. Rapid acinar to ductal transdifferentiation in cultured human exocrine pancreas. J. Pathol. 166, 97–103 (1992).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hendley, A. M. et al. p120 Catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas. Dev. Biol. 399, 41–53 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Criscimanna, A., Coudriet, G. M., Gittes, G. K., Piganelli, J. D. & Esni, F. Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and beta-cell regeneration in mice. Gastroenterology 147, 1106–1118.e11 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Kowalik, A. S. et al. Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1123–G1132 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Karki, A. et al. Silencing Mist1 gene expression is essential for recovery from acute pancreatitis. PLoS ONE 10, e0145724 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Fendrich, V. et al. Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology 135, 621–631 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kong, B. et al. Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy. Gut http://dx.doi.org/10.1136/gutjnl-2015-310913 (2016).

  80. Baer, R. 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  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wu, C. Y. et al. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology 147, 1405–1416.e7 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Payne, S. N. 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 

  83. Collins, M. A., Yan, W., Sebolt-Leopold, J. S. & Pasca di Magliano, M. MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology 146, 822–834.e7 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Heid, I. et al. Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology 141, 719–730.e7 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Xu, H. N., Nioka, S., Chance, B. & Li, L. Z. Heterogeneity of mitochondrial redox state in premalignant pancreas in a PTEN null transgenic mouse model. Adv. Exp. Med. Biol. 701, 207–213 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hill, R. et al. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res. 70, 7114–7124 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Eser, S. et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23, 406–420 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Elghazi, L. et al. Regulation of pancreas plasticity and malignant transformation by Akt signaling. Gastroenterology 136, 1091–1103 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Albury, T. M. et al. Constitutively active Akt1 cooperates with KRasG12D to accelerate in vivo pancreatic tumor onset and progression. Neoplasia 17, 175–182 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Weiss, G. A. et al. Evaluation of phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) and epidermal growth factor receptor (EGFR) gene mutations in pancreaticobiliary adenocarcinoma. J. Gastrointest. Oncol. 4, 20–29 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  92. Maniati, E. et al. Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. J. Clin. Invest. 121, 4685–4699 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Palagani, V. et al. Combined inhibition of Notch and JAK/STAT is superior to monotherapies and impairs pancreatic cancer progression. Carcinogenesis 35, 859–866 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Carriere, C., Young, A. L., Gunn, J. R., Longnecker, D. S. & Korc, M. Acute pancreatitis accelerates initiation and progression to pancreatic cancer in mice expressing oncogenic Kras in the nestin cell lineage. PLoS ONE 6, e27725 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Shi, C. 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 

  96. Huang, H. et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene 33, 532–535 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. Clark, C. E., Beatty, G. L. & Vonderheide, R. H. Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett. 279, 1–7 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Rosati, A. et al. BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages. Nat. Commun. 6, 8695 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Makohon-Moore, A. & Iacobuzio-Donahue, C. A. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat. Rev. Cancer 16, 553–565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012). The authors show that previously tagged pancreatic epithelial cells invade and enter the blood stream at a stage when malignancy could not be detected by histological means. A majority of the circulating pancreatic epithelial cells express DCLK1 as a marker.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rhim, A. D. et al. Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology 146, 647–651 (2014).

    Article  PubMed  Google Scholar 

  103. Bailey, J. M. et al. DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 146, 245–256 (2014). In this paper, Bailey et al . show that precancerous lesions contain a subpopulation of cells positive for DCLK1. Using lineage tracing they demonstrate the acinar origin of these DCLK-positive cells.

    Article  CAS  PubMed  Google Scholar 

  104. Qu, D. et al. Doublecortin-like kinase 1 is elevated serologically in pancreatic ductal adenocarcinoma and widely expressed on circulating tumor cells. PLoS ONE 10, e0118933 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Delgiorno, K. E. et al. Identification and manipulation of biliary metaplasia in pancreatic tumors. Gastroenterology 146, 233–244.e5 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Westphalen, C. B. 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 

  108. Basturk, O. et al. A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 39, 1730–1741 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Newman, K. et al. Pancreatic carcinoma with multilineage (acinar, neuroendocrine, and ductal) differentiation. Int. J. Clin. Exp. Pathol. 2, 602–607 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Esposito, I. et al. Hypothetical progression model of pancreatic cancer with origin in the centroacinar-acinar compartment. Pancreas 35, 212–217 (2007).

    Article  PubMed  Google Scholar 

  111. Tanaka, M. et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 12, 183–197 (2012).

    Article  PubMed  Google Scholar 

  112. Strobel, O. 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. USA 104, 4419–4424 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Grippo, P. J., Nowlin, P. S., Demeure, M. J., Longnecker, D. S. & Sandgren, E. P. 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 

  114. Sanchez-Munoz, A. et al. Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer. BMC Cancer 10, 136 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tuveson, D. A. 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 

  116. Habbe, N. et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA 105, 18913–18918 (2008).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  118. Real, F. X. A “catastrophic hypothesis” for pancreas cancer progression. Gastroenterology 124, 1958–1964 (2003).

    Article  PubMed  Google Scholar 

  119. Ohlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks H. R. Döppler and V. Pandey in the Storz laboratory for critical reading of the manuscript. The author apologizes to colleagues whose papers, although important contributions to the field, have not been cited because of the scope of this Review. This work was supported by grants from the NIH (CA200572 and CA102701-12DRP3).

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Room 306 Griffin Building, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, 32224, Florida, USA

    Peter Storz

Authors
  1. Peter Storz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Storz.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Storz, P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 14, 296–304 (2017). https://doi.org/10.1038/nrgastro.2017.12

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2017.12

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing