Krasmutation rate precisely orchestrates ductal derived pancreatic intraepithelial neoplasia and pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence ofKrasmutations in pancreatic cancer patients, murine models expressing the oncogenic mutantKras(Kras(mut)) in mature pancreatic cells develop PDAC at a low frequency. Independent of cell of origin, a second genetic hit (loss of tumor suppressorTP53orPTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutantKraswould promote PanIN arising in pancreatic ducts. To test our hypothesis, the significance of elevating levels of K-Ras and Ras activity has been explored by expression of a CAG drivenLGSL-Kras(G12V)allele (cKras) in pancreatic ducts, which promotes ectopicKrasexpression. We predicted expression ofcKrasin pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreER(T2)mediated recombination.Hnf1b:CreER(T2);Kras(G12V)(cKras(Hnf1b/+)) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombinecKrasin low (cKras(Low)), moderate (cKras(Mod)), and high (cKras(High)) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors incKras(High)mice.cKras(Mod)mice had grades of Pancreatic Intraepithelial Neoplasia (PanIN), recapitulating early and advanced PanIN observed in human PDAC. Proteomics analysis revealed significant differences in PTEN/AKT and MAPK pathways between wild type,cKras(Low),cKras(Mod), andcKras(High)mice. In conclusion, in this study, we provide evidence that ectopic expression of oncogenic mutant K-Ras in pancreatic ducts generates early and late PanIN as well as PDAC. This Ras rheostat model provides evidence that AKT signaling is an important early driver of invasive ductal derived PDAC. In this study, the authors provide evidence that ectopic expression of oncogenic mutantKrasin pancreatic ducts generates early and late (PanIN) and pancreatic ductal adenocarcinoma (PDAC) . They characterized this Ras rheostat model which reveals elevatedKrasmutation frequency and loss of PTEN are important drivers of PanIN and invasive ductal derived PDAC.