期刊
GENES & DEVELOPMENT
卷 28, 期 23, 页码 2621-2635出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.249409.114
关键词
genetic mouse models; PI3K isoforms; pancreas; oncogenes; signaling; transdifferentiation
资金
- LNCC [JG/VSP-8949, GB/MA/VSP-10443, 7FI10193LQJY]
- EU-ERG FP7 [270696-PaCa/PI3K]
- GSOEmergence [R14040BB/RPL14007BBA]
- Arc [SFI20101201616]
- Labelisation LNCC Team6-CRCT
- Universite Toulouse III Emergence
- Deutsche Forschungsgemeinschaft [SA 1374/4-1, SFB824 TPC9]
- Helmholtz Alliance Preclinical Comprehensive Cancer Center
- Cancer Research UK [15965] Funding Source: researchfish
Increased PI 3-kinase (PI3K) signaling in pancreatic ductal adenocarcinoma (PDAC) correlates with poor prognosis, but the role of class I PI3K isoforms during its induction remains unclear. Using genetically engineered mice and pharmacological isoform-selective inhibitors, we found that the p110 alpha PI3K isoform is a major signaling enzyme for PDAC development induced by a combination of genetic and nongenetic factors. Inactivation of this single isoform blocked the irreversible transition of exocrine acinar cells into pancreatic preneoplastic ductal lesions by oncogenic Kras and/or pancreatic injury. Hitting the other ubiquitous isoform, p110 beta, did not prevent preneoplastic lesion initiation. p110 alpha signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110 alpha was necessary for pancreatic ductal cancers to arise from Kras-induced preneoplastic lesions by increasing epithelial cell proliferation in the context of mutated p53. Here we identify an in vivo context in which p110 alpha cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110 alpha is required for PDAC induced by oncogenic Kras, the key driver mutation of PDAC. These data are critical for a better understanding of the development of this lethal disease that is currently without efficient treatment.
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