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KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma

Key Points

  • Mutations in KRAS are nearly universal in human pancreatic ductal adenocarcinoma (PDAC). Mouse models in which mutant KRAS is targeted to the pancreas reveal that KRAS signalling is sufficient to reprogram pancreatic cells into duct-like lineages capable of progressing through preneoplastic lesions and, ultimately, PDAC in stages that are reminiscent of human disease.

  • The latency, differentiation and type of preneoplastic lesion observed in KRAS-driven PDAC mouse models is sensitive to tumour suppressor loss, suggesting that PDAC evolution is dependent on sequential tuning of signalling pathways.

  • PDAC is characterized by frequent deregulation of embryonic signalling pathways, including Hedgehog (Hh) and Wnt–β-catenin signalling. Recent evidence points to temporal and spatial control of these pathways in PDAC development and maintenance.

  • PDAC cells frequently display aberrant Hh ligand expression. Recent studies suggest that classical ligand-dependent signalling is activated in cells in the tumour microenvironment, supporting tumour maintenance in a paracrine fashion, but not in the tumour epithelium. However, Hh signalling at the level of Gli transcriptional factors is active in the tumour epithelium, dictated by non-canonical regulators of the pathway. Both paracrine ligand activity and epithelial Gli signalling seem to independently support KRAS-driven PDAC evolution in mouse models.

  • Wnt–β-catenin signalling is frequently activated in PDAC and contributes to tumour cell proliferation and biology. Genetic models that allow Wnt–β-catenin deregulation reveal that this pathway can transform pancreatic cells but is insufficient to drive PDAC initiation.

  • Mouse models have revealed that the ability of KRAS to reprogram cells into a duct-like fate that can give rise to PDAC is sensitive to cell differentiation and levels of KRAS signalling. Temporal regulation of embryonic signalling pathways seems to play a part in preneoplastic reprogramming, as shown by a requirement for control of Wnt–β-catenin signalling during KRAS-driven de-differentiation of acinar cells into PDAC precursor lesions.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by near-universal mutations in KRAS and frequent deregulation of crucial embryonic signalling pathways, including the Hedgehog (Hh) and Wnt–β-catenin cascades. The creation of mouse models that closely resemble the human disease has provided a platform to better understand when and in which cell types these pathways are misregulated during PDAC development. Here we examine the central part that KRAS plays in the biology of PDAC, and how the timing and location of Hh and Wnt–β-catenin signalling dictate the specification and oncogenic properties of PDAC.

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Figure 1: KRAS is a master regulator of pancreatic ductal adenocarcinoma initiation and progression.
Figure 2: Hedgehog signalling in pancreatic ductal adenocarcinoma.
Figure 3: Canonical Wnt–β-catenin signalling in pancreatic ductal adencocarcinoma.
Figure 4: Crucial temporal thresholds of developmental signalling pathways and KRAS activity allow pancreatic epithelial neoplasia — pancreatic ductal adenocarcinoma initiation and progression.

References

  1. Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. & Depinho, R. A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).

    CAS  PubMed  Article  Google Scholar 

  2. Corcoran, R. B. & Scott, M. P. A mouse model for medulloblastoma and basal cell nevus syndrome. J. Neurooncol. 53, 307–318 (2001).

    CAS  PubMed  Article  Google Scholar 

  3. Romer, J. T. et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/− p53−/− mice. Cancer Cell 6, 229–240 (2004).

    CAS  PubMed  Article  Google Scholar 

  4. Taketo, M. M. & Edelmann, W. Mouse models of colon cancer. Gastroenterology 136, 780–798 (2009).

    CAS  PubMed  Article  Google Scholar 

  5. Habbe, N., Langer, P., Sina-Frey, M. & Bartsch, D. K. Familial pancreatic cancer syndromes. Endocrinol. Metab. Clin. North Am. 35, 417–430 (2006).

    CAS  PubMed  Article  Google Scholar 

  6. Wescott, M. P. & Rustgi, A. K. Pancreatic cancer: translating lessons from mouse models and hereditary syndromes. Cancer Prev. Res. 1, 503–506 (2008).

    CAS  Article  Google Scholar 

  7. Almoguera, C. et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53, 549–554 (1988).

    CAS  PubMed  Article  Google Scholar 

  8. Caldas, C. et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nature Genet. 8, 27–32 (1994).

    CAS  PubMed  Article  Google Scholar 

  9. Ruggeri, B. et al. Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and Rb-1 tumor-suppressor genes. Oncogene 7, 1503–1511 (1992).

    CAS  PubMed  Google Scholar 

  10. Scarpa, A. et al. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am. J. Pathol. 142, 1534–1543 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996).

    CAS  PubMed  Article  Google Scholar 

  12. Rodriguez-Viciana, P. et al. Cancer targets in the Ras pathway. Cold Spring Harb. Symp. Quant. Biol. 70, 461–467 (2005).

    CAS  PubMed  Article  Google Scholar 

  13. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Hruban, R. H., Maitra, A., Kern, S. E. & Goggins, M. Precursors to pancreatic cancer. Gastroenterol. Clin. North Am. 36, 831–849, vi (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  15. Hruban, R. H. 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).

    PubMed  Article  Google Scholar 

  16. Feldmann, G., Beaty, R., Hruban, R. H. & Maitra, A. Molecular genetics of pancreatic intraepithelial neoplasia. J. Hepatobiliary Pancreat. Surg. 14, 224–232 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  17. Lohr, M., Kloppel, G., Maisonneuve, P., Lowenfels, A. B. & Luttges, J. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia 7, 17–23 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. Maitra, A. et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod. Pathol. 16, 902–912 (2003).

    PubMed  Article  Google Scholar 

  19. Wilentz, R. E. et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 60, 2002–2006 (2000).

    CAS  PubMed  Google Scholar 

  20. 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 

  21. Brembeck, F. H. 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 

  22. Tuveson, D. A. et al. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).

    CAS  Article  PubMed  Google Scholar 

  23. Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003). The first example of a conditional Kras - driven PDAC mouse model that recapitulates the progression observed in humans.

    CAS  PubMed  Article  Google Scholar 

  24. 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). The first direct functional demonstration that PDAC can arise from non-ductal cells. This paper also established a functional link between pancreatitis and PDAC initiation and progression.

    CAS  PubMed  Article  Google Scholar 

  25. 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). This study provided evidence that mutant Kras is sufficient to reprogram acini into the PanIN lineage in the absence of tissue damage.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  28. Ji, B. et al. Ras activity levels control the development of pancreatic diseases. Gastroenterology 137, 1072–1082, e6 (2009).

    CAS  PubMed  Article  Google Scholar 

  29. Morris, J. P. 4th, Cano, D. A., Sekine, S., Wang, S. C. & Hebrok, M. β-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009). This study provided evidence that mutant Kras combined with chronic pancreatitis can drive endocrine cells into the PanIN–PDAC lineage.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Bardeesy, N. et al. Both p16Ink4a and the p19Arf–p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc. Natl Acad. Sci. USA 103, 5947–5952 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005). Mutant p53 drives both PDAC progression and the development of metastasis and genomic instability, which are hallmarks of the human disease.

    CAS  Article  PubMed  Google Scholar 

  34. Bardeesy, N. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Ijichi, H. et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression. Genes Dev. 20, 3147–3160 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Izeradjene, K. et al. KrasG12D and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11, 229–243 (2007).

    CAS  PubMed  Article  Google Scholar 

  37. Kojima, K. et al. Inactivation of Smad4 accelerates KrasG12D-mediated pancreatic neoplasia. Cancer Res. 67, 8121–8130 (2007).

    CAS  PubMed  Article  Google Scholar 

  38. Vincent, D. F. et al. Inactivation of TIF1γ cooperates with Kras to induce cystic tumors of the pancreas. PLoS Genet. 5, e1000575 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. Quint, E. et al. Bone patterning is altered in the regenerating zebrafish caudal fin after ectopic expression of sonic hedgehog and bmp2b or exposure to cyclopamine. Proc. Natl Acad. Sci. USA 99, 8713–8718 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. Karhadkar, S. S. et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004).

    CAS  PubMed  Article  Google Scholar 

  41. Stecca, B. & Ruiz i Altaba, A. Brain as a paradigm of organ growth: Hedgehog–Gli signaling in neural stem cells and brain tumors. J. Neurobiol. 64, 476–490 (2005).

    CAS  PubMed  Article  Google Scholar 

  42. Liu, S. et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66, 6063–6071 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Li, N. et al. Reciprocal intraepithelial interactions between TP63 and hedgehog signaling regulate quiescence and activation of progenitor elaboration by mammary stem cells. Stem Cells 26, 1253–1264 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Hooper, J. E. & Scott, M. P. Communicating with Hedgehogs. Nature Rev. Mol. Cell Biol. 6, 306–317 (2005).

    CAS  Article  Google Scholar 

  45. Jiang, J. & Hui, C. C. Hedgehog signaling in development and cancer. Dev. Cell 15, 801–812 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Pan, Y., Bai, C. B., Joyner, A. L. & Wang, B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol. Cell. Biol. 26, 3365–3377 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423–434 (2000).

    CAS  PubMed  Article  Google Scholar 

  48. Kenney, A. M. & Rowitch, D. H. Sonic hedgehog promotes G1 cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol. Cell. Biol. 20, 9055–9067 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Mill, P. et al. Shh controls epithelial proliferation via independent pathways that converge on N-Myc. Dev. Cell 9, 293–303 (2005).

    CAS  PubMed  Article  Google Scholar 

  50. Regl, G. et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 64, 7724–7731 (2004).

    CAS  PubMed  Article  Google Scholar 

  51. Teh, M. T. et al. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res. 62, 4773–4780 (2002).

    CAS  PubMed  Google Scholar 

  52. Brancaccio, A. et al. Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis. Hum. Mol. Genet. 13, 2595–2606 (2004).

    CAS  PubMed  Article  Google Scholar 

  53. Rubin, L. L. & de Sauvage, F. J. Targeting the Hedgehog pathway in cancer. Nature Rev. Drug Discov. 5, 1026–1033 (2006).

    CAS  Article  Google Scholar 

  54. Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

    CAS  Article  PubMed  Google Scholar 

  55. Xie, J. et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90–92 (1998).

    CAS  Article  PubMed  Google Scholar 

  56. Raffel, C. et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 57, 842–845 (1997).

    CAS  PubMed  Google Scholar 

  57. Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003). Hh ligands are frequently overexpressed in human PDAC, and enforced Hh ligand expression during pancreatic development can lead to elements of PDAC initiation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Feldmann, G. et al. An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol. Cancer Ther. 7, 2725–2735 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Feldmann, G. et al. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 57, 1420–1430 (2008).

    CAS  PubMed  Article  Google Scholar 

  60. Feldmann, G. et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 67, 2187–2196 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009). SMO inhibition increases accessibility of chemotherapeutic agents and decreases the fibroblast compartment in a mouse model of PDAC.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Yauch, R. L. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406–410 (2008). PDAC cells do not respond to Hh ligand or SMO inhibition. This study provides evidence that Hh ligand activates the signalling cascade in cells in the tumour microenvironment, providing paracrine tumour support.

    CAS  PubMed  Article  Google Scholar 

  63. Tian, H. et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc. Natl Acad. Sci. USA 106, 4254–4259 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nature Rev. Cancer 6, 392–401 (2006).

    CAS  Article  Google Scholar 

  65. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

  66. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    CAS  PubMed  Article  Google Scholar 

  67. Bachem, M. G. et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907–921 (2005).

    CAS  PubMed  Article  Google Scholar 

  68. Hwang, R. F. et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918–926 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Vonlaufen, A. et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 68, 2085–2093 (2008).

    CAS  PubMed  Article  Google Scholar 

  70. Bailey, J. M., Mohr, A. M. & Hollingsworth, M. A. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene 28, 3513–3525 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Bailey, J. M. et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin. Cancer Res. 14, 5995–6004 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Menke, A. et al. Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Cancer Res. 61, 3508–3517 (2001).

    CAS  PubMed  Google Scholar 

  73. Armstrong, T. et al. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 10, 7427–7437 (2004).

    CAS  PubMed  Article  Google Scholar 

  74. Shintani, Y., Hollingsworth, M. A., Wheelock, M. J. & Johnson, K. R. Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH2-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res. 66, 11745–11753 (2006).

    CAS  PubMed  Article  Google Scholar 

  75. Koenig, A., Mueller, C., Hasel, C., Adler, G. & Menke, A. Collagen type I induces disruption of E-cadherin-mediated cell–cell contacts and promotes proliferation of pancreatic carcinoma cells. Cancer Res. 66, 4662–4671 (2006).

    CAS  PubMed  Article  Google Scholar 

  76. Nakamura, K. et al. Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells. PLoS ONE 5, e8824 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. Burris, H. A. . et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997).

    CAS  Article  PubMed  Google Scholar 

  78. Tempero, M. et al. Randomized Phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J. Clin. Oncol. 21, 3402–3408 (2003).

    CAS  PubMed  Article  Google Scholar 

  79. Tsuda, N. et al. Synthetic microRNA designed to target glioma-associated antigen 1 transcription factor inhibits division and induces late apoptosis in pancreatic tumor cells. Clin. Cancer Res. 12, 6557–6564 (2006).

    CAS  PubMed  Article  Google Scholar 

  80. Lauth, M., Bergstrom, A., Shimokawa, T. & Toftgard, R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc. Natl Acad. Sci. USA 104, 8455–8460 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. Nolan-Stevaux, O. et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 23, 24–36 (2009). KRAS-driven PDAC develops in the absence of smoothened expression. However, aberrant Hh ligand expression and epithelial Gli signalling remain present, suggesting that they are uncoupled during PDAC development.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Ji, Z., Mei, F. C., Xie, J. & Cheng, X. Oncogenic KRAS activates Hedgehog signaling pathway in pancreatic cancer cells. J. Biol. Chem. 282, 14048–14055 (2007).

    CAS  PubMed  Article  Google Scholar 

  83. Dennler, S. et al. Induction of sonic hedgehog mediators by transforming growth factor-β: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 67, 6981–6986 (2007).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  85. Pasca di Magliano, M. et al. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 20, 3161–3173 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Clevers, H. Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    CAS  PubMed  Article  Google Scholar 

  87. MacDonald, B. T., Tamai, K. & He, X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Schwartz, A. L. et al. Phenylmethimazole decreases Toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin. Cancer Res. 15, 4114–4122 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Pilarsky, C. et al. Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling. J. Cell. Mol. Med. 12, 2823–2835 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Segditsas, S. & Tomlinson, I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25, 7531–7537 (2006).

    CAS  Article  PubMed  Google Scholar 

  91. Seymour, A. B. et al. Allelotype of pancreatic adenocarcinoma. Cancer Res. 54, 2761–2764 (1994).

    CAS  PubMed  Google Scholar 

  92. Gerdes, B. et al. Analysis of β-catenin gene mutations in pancreatic tumors. Digestion 60, 544–548 (1999).

    CAS  PubMed  Article  Google Scholar 

  93. Abraham, S. C. et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor β-catenin mutations. Am. J. Pathol. 160, 1361–1369 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Al-Aynati, M. M., Radulovich, N., Riddell, R. H. & Tsao, M. S. Epithelial-cadherin and β-catenin expression changes in pancreatic intraepithelial neoplasia. Clin. Cancer Res. 10, 1235–1240 (2004).

    CAS  PubMed  Article  Google Scholar 

  95. Zeng, G. et al. Aberrant Wnt/β-catenin signaling in pancreatic adenocarcinoma. Neoplasia 8, 279–289 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Pasca di Magliano, M. et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS ONE 2, e1155 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. Wang, L. et al. Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and β-catenin stabilization. Cancer Cell 15, 207–219 (2009). Cell autonomous ATDC supports β-catenin accumulation and signalling during PDAC development and impacts tumour cell proliferation and transformed characteristics.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Froeling, F. E. et al. Organotypic culture model of pancreatic cancer demonstrates that stromal cells modulate E-cadherin, β-catenin, and Ezrin expression in tumor cells. Am. J. Pathol. 175, 636–648 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Nawroth, R. et al. Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS ONE 2, e392 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. Takahashi, N. et al. Dickkopf-1 is overexpressed in human pancreatic ductal adenocarcinoma cells and is involved in invasive growth. Int. J. Cancer 126, 1611–1620 (2009).

    Google Scholar 

  101. Kemler, R. et al. Stabilization of β-catenin in the mouse zygote leads to premature epithelial–mesenchymal transition in the epiblast. Development 131, 5817–5824 (2004).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  103. Strom, A. et al. Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas. Development 134, 2719–2725 (2007).

    CAS  PubMed  Article  Google Scholar 

  104. Heiser, P. W. et al. Stabilization of β-catenin induces pancreas tumor formation. Gastroenterology 135, 1288–1300 (2008).

    CAS  PubMed  Article  Google Scholar 

  105. Nishimori, I. et al. Non-cystic solid-pseudopapillary tumor of the pancreas showing nuclear accumulation and activating gene mutation of β-catenin. Pathol. Int. 56, 707–711 (2006).

    CAS  PubMed  Article  Google Scholar 

  106. Janssen, K. P. et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 131, 1096–1109 (2006).

    CAS  PubMed  Article  Google Scholar 

  107. Phelps, R. A. et al. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 137, 623–634 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Sansom, O. J. et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc. Natl Acad. Sci. USA 103, 14122–14127 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. Lowenfels, A. B. et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N. Engl. J. Med. 328, 1433–1437 (1993).

    CAS  PubMed  Article  Google Scholar 

  110. Malka, D. et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 51, 849–852 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Hassan, M. M. et al. Risk factors for pancreatic cancer: case–control study. Am. J. Gastroenterol. 102, 2696–2707 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  112. Fendrich, V. et al. Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology 135, 621–631 (2008). This study demonstrated that acinar cells regenerate from pre-existing acinar cells through ductal intermediates following chemically induced pancreatitis.

    CAS  PubMed  Article  Google Scholar 

  113. Jensen, J. N. et al. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology 128, 728–741 (2005). This study provided evidence that embryonic signalling pathways are reactivated during acinar regeneration following chemically induced pancreatitis.

    CAS  PubMed  Article  Google Scholar 

  114. Desai, B. M. et al. Preexisting pancreatic acinar cells contribute to acinar cell, but not islet β cell, regeneration. J. Clin. Invest. 117, 971–977 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Siveke, J. T. et al. Concomitant pancreatic activation of KrasG12D and Tgfa results in cystic papillary neoplasms reminiscent of human IPMN. Cancer Cell 12, 266–279 (2007).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  118. Carriere, C., Young, A. L., Gunn, J. R., Longnecker, D. S. & Korc, M. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem. Biophys. Res. Commun. 382, 561–565 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Siveke, J. T. et al. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 134, 544–555 (2008).

    CAS  PubMed  Article  Google Scholar 

  120. Strobel, O. et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 133, 1999–2009 (2007).

    PubMed  Article  Google Scholar 

  121. Strobel, O. et al. Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia. Gastroenterology 138, 1166–1177.

    PubMed  Article  Google Scholar 

  122. Means, A. L. et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132, 3767–3776 (2005).

    CAS  PubMed  Article  Google Scholar 

  123. Miyamoto, Y. et al. Notch mediates TGF α-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3, 565–576 (2003).

    CAS  PubMed  Article  Google Scholar 

  124. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Hanlon, L. et al. Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res. 70, 4280–4286 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Hruban, R. H., Goggins, M., Parsons, J. & Kern, S. E. Progression model for pancreatic cancer. Clin. Cancer Res. 6, 2969–2972 (2000).

    CAS  PubMed  Google Scholar 

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

    PubMed  Article  PubMed Central  CAS  Google Scholar 

  130. Mao, J. et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 66, 10171–10178 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Romero, D., Iglesias, M., Vary, C. P. & Quintanilla, M. Functional blockade of Smad4 leads to a decrease in β-catenin levels and signaling activity in human pancreatic carcinoma cells. Carcinogenesis 29, 1070–1076 (2008).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

The authors thank R. Vanderlaan and A. Folias for critical reading of the manuscript and stimulating discussions. Work in the M.H. laboratory on pancreatic cancer is supported by grants from the National Institutes of Health (NIH) (CA112537) and American Association for Cancer Research Pancreatic Cancer Network (PanCAN). S.C.W. is supported by the NIH under the Ruth L. Kirschstein National Research Service Award F32 from the National Cancer Institute and the American College of Surgeons Resident Research Scholarship.

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Pathway Interaction Database 

Wnt–β-catenin

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Morris, J., Wang, S. & Hebrok, M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer 10, 683–695 (2010). https://doi.org/10.1038/nrc2899

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