Ductal pancreatic adenocarcinoma is almost uniformly lethal and cannot be effectively detected at early stages. Virtually all cases of pancreatic cancer and preneoplastic ductal hyperplasias contain oncogenic Kras mutations, suggesting its importance in this disease. Animal models of cancer that faithfully recapitulate the cognate human condition afford the opportunity to explore the molecular basis of cancer, develop early detection strategies, and evaluate novel therapies. Although mutant mice predisposed to the development of exocrine pancreatic cancer have been previously described, none develop ductal pancreatic adenocarcinoma resembling the human disease. In order to construct a more relevant murine model of ductal pancreatic cancer, we have engineered a mutant mouse strain that harbors an endogenous, conditionally-expressed, oncogenic K-ras G12D allele. By crossing this strain with mouse strains that express Cre recombinase in the pancreas, we observe preneoplastic pancreatic ductal lesions (PanlN) that strikingly resemble those seen in humans. Here, we will investigate the cellular compartments that are capable of initiating pancreatic cancer, determine the relative importance of the two tumor suppressor genes in the Ink4a/ARF locus with regards to tumor progression, and evaluate the role of Notch signaling and MMP7 function in the development of PanlN and PDA. The availability of a suitable murine model of pancreatic ductal adenocarcinoma will allow a detailed assessment of the molecular and cellular features present in discrete stages of tumorigenesis. Such studies are essentially impossible in human pancreatic cancer specimens since they are invariably detected only at very late stages. Information gained from this murine model should facilitate further understanding of human pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101973-02
Application #
6916463
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Mietz, Judy
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$306,455
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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