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

Autor: Singh, Kanchan, Pruski, Melissa, Bland, Rachael, Younes, Mamoun, Guha, Sushovan, Thosani, Nirav, Maitra, Anirban, Cash, Brooks D., McAllister, Florencia, Logsdon, Craig D., Chang, Jeffrey T., Bailey-Lundberg, Jennifer M.
Zdroj: Laboratory Investigation; February 2021, Vol. 101 Issue: 2 p177-192, 16p
Abstrakt: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Krasmutations in pancreatic cancer patients, murine models expressing the oncogenic mutant Kras(Krasmut) in mature pancreatic cells develop PDAC at a low frequency. Independent of cell of origin, a second genetic hit (loss of tumor suppressor TP53or PTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutant Kraswould 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 driven LGSL-KrasG12Vallele (cKras) in pancreatic ducts, which promotes ectopic Krasexpression. We predicted expression of cKrasin pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreERT2mediated recombination. Hnf1b:CreERT2;KrasG12V(cKrasHnf1b/+) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombine cKrasin low (cKrasLow), moderate (cKrasMod), and high (cKrasHigh) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors in cKrasHighmice. cKrasModmice 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, cKrasLow, cKrasMod, and cKrasHighmice. 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.
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