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Author Notes:

Address correspondence to: Marina Pasca di Magliano, Department of Surgery and Cell and Developmental Biology, 1500 E Medical Center Drive, Ann Arbor, Michigan 48109-5936, USA. Phone: 734.615.7424; Fax: 734.647.9654; E-mail: marinapa@umich.edu

We would like to thank Diane Simeone, Anj Dlugosz, Jörg Zeller, Ben Allen, and Mats Ljungman (University of Michigan, Ann Arbor) for scientific discussion and critical reading of the manuscript.

We thank Jimmy Hogan, Ace Josifoki, and Beth Skendrovich for help with immunostaining and histology. The p48-Cre (Ptf1a-Cre) mouse was a gift from Chris Wright (Vanderbilt University).

The CK19 antibody (Troma III) was obtained from the Iowa Developmental Hybridoma Bank.

The Hes1 antibody was a gift from Ben Stanger (University of Pennsylvania, Philadelphia, Pennsylvania, USA).

The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

Work in the Pasca di Magliano laboratory is supported by the University of Michigan Biological Scholar Program, NCI 1R01CA151588-01, GI SPORE P50 CA 13810, a Pancreatic Cancer Action Network (PanCan)/American Association for Cancer Research (AACR) Career Development grant, and the Michigan Gastrointestinal Peptide Research Center (P30 DK 034933-25).

M.A. Collins is supported by a University of Michigan Program in Cellular and Molecular Biology training grant (NIH T32 GM07315) and by a University of Michigan Center for Organogenesis training grant (5-T32-HD007515).

F. Bednar is supported by the American College of Surgeons Resident Research Scholarship and by NIH T32 HD007505.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • MEDICINE, RESEARCH & EXPERIMENTAL
  • DUCTAL ADENOCARCINOMA
  • K-RAS
  • INTRAEPITHELIAL NEOPLASIA
  • MOUSE MODELS
  • PATHWAY ACTIVATION
  • ADULT MICE
  • HEDGEHOG
  • EXPRESSION
  • INDUCTION
  • TUMORIGENESIS

Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice

Tools:

Journal Title:

Journal of Clinical Investigation

Volume:

Volume 122, Number 2

Publisher:

, Pages 639-653

Type of Work:

Article | Final Publisher PDF

Abstract:

Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRAS G12D , that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible Kras G12D , which allows for inducible, pancreas-specific, and reversible expression of the oncogenic Kras G12D , with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic Kras G12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of Kras G12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that Kras G12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, Kras G12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial Kras G12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting Kras G12D , or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer.

Copyright information:

© 2012, American Society for Clinical Investigation

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