Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis.

Journal Article (Journal Article)

BACKGROUND & AIMS: Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC), but how it synergizes with KRAS mutation is not known. METHODS: We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells. RESULTS: Although KrasG12D expression in both cell types was protective against damage-associated cell death, chronic pancreatitis induced p53, p21, and growth arrest only in acinar-derived cells. Mutant duct cells did not elevate p53 or p21 expression and exhibited increased proliferation driving the appearance of PDAC over time. CONCLUSIONS: One mechanism by which tissues may be susceptible or resistant to KRASG12D-initiated tumorigenesis is whether they undergo a p53-mediated damage response. In summary, we have uncovered a mechanism by which inflammation and intrinsic cellular programming synergize for the development of PDAC.

Full Text

Duke Authors

Cited Authors

  • Shi, C; Pan, FC; Kim, JN; Washington, MK; Padmanabhan, C; Meyer, CT; Kopp, JL; Sander, M; Gannon, M; Beauchamp, RD; Wright, CV; Means, AL

Published Date

  • 2019

Published In

Volume / Issue

  • 8 / 4

Start / End Page

  • 579 - 594

PubMed ID

  • 31310834

Pubmed Central ID

  • 31310834

Electronic International Standard Serial Number (EISSN)

  • 2352-345X

Digital Object Identifier (DOI)

  • 10.1016/j.jcmgh.2019.07.001

Language

  • eng

Conference Location

  • United States