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

Nature Reviews Cancer volume 10, pages 683–695 (2010)Cite this article

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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.

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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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  1. Diabetes Center, University of California, San Francisco, 513 Parnassus Ave, San Francisco, 94143, California, USA

    John P. Morris IV, Sam C. Wang & Matthias Hebrok

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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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