Abstract
AbstractPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Kras mutations 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 TP53 or PTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutant Kras would 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-KrasG12V allele (cKras) in pancreatic ducts, which promotes ectopic Kras expression. We predicted expression of cKras in pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreERT2 mediated recombination. Hnf1b:CreERT2;KrasG12V (cKrasHnf1b/+) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombine cKras in low (cKrasLow), moderate (cKrasMod), and high (cKrasHigh) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors in cKrasHigh mice. cKrasMod 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, cKrasLow, cKrasMod, and cKrasHigh 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. SummaryIn this study, the authors provide evidence that ectopic expression of oncogenic mutant Kras in pancreatic ducts generates early and late (PanIN) and pancreatic ductal adenocarcinoma (PDAC) . They characterized this Ras rheostat model which reveals elevated Kras mutation frequency and loss of PTEN are important drivers of PanIN and invasive ductal derived PDAC.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Cell of origin differences have been shown to promote molecular heterogeneity in a number of malignancies [1, 2]
green fluorescent protein (GFP) immunolabeling significantly increased in centroacinar and intercalated ducts in mTmGHnf1b/+ High mice with an average count of 41/field compared to mTmGHnf1b/+ Low (13/field) or mTmGHnf1b/+ Mod (32/field) mice. mTmGHnf1b/+ Mod mice had significantly higher numbers of recombined centroacinar cells and intercalated ducts than mTmGHnf1b/+ Low mice (P < 0.001). g When analyzing recombination in main pancreatic and intralobular ducts, we observed a significant increase in mTmGHnf1b/+ Mod (58% ducts/field) and mTmGHnf1b/+ High (92% of ducts/field) mice compared to mTmGHnf1b/+ Low mice (11% ducts/field)
In the context of ductal adenocarcinoma of the pancreas, recent mouse models have shown that pancreatic ductal cells can serve as the cell of origin of Pancreatic ductal adenocarcinoma (PDAC) when Kras is mutated and, from the onset of oncogenic Krasmut expression, Trp53, Fbw7, or Pten are genetically deleted, or a gain of function mutant of Trp53 is expressed, using Hnf1b:CreERT2, Sox9:CreER, or Ck19:CreER driver lines
Summary
Understanding the biology of how exocrine pancreatic cells transform to cancer is important for development of targeted therapeutic approaches for prevention of aggressive disease. PDAC is preceded by precursor lesions postulated to arise from pancreatic exocrine epithelium. A well-established autochthonous mouse model has shown PanIN arise in the setting of physiologic expression of KrasG12D in Pdx (or Ptf1a/p48) expressing multipotent pancreatic progenitors. In this model, at 9 months of age, mice display the full histological spectrum of early and advanced PanIN lesions [16]. Adult pancreatic exocrine cells are refractory to oncogenic Krasmut induced invasive carcinoma when KrasG12D is expressed under endogenous promoter elements unless there is induced inflammation or concomitant loss of a tumor suppressor gene [17,18,19,20,21,22]
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