Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult Mice

Summary Pancreatic ductal adenocarcinoma (PDA), one of the deadliest human cancers, often involves somatic activation of K- Ras oncogenes. We report that selective expression of an endogenous K- Ras G12V oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells. Surprisingly, adult mice become refractory to K- Ras G12V -induced PanINs and PDA. However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA. These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K- Ras mutations) and nongenetic (e.g., tissue damage) events.