| Literature DB >> 32976774 |
Linara Gabitova-Cornell1, Aizhan Surumbayeva1, Suraj Peri2, Janusz Franco-Barraza3, Diana Restifo1, Nicole Weitz1, Charline Ogier1, Aaron R Goldman4, Tiffiney R Hartman5, Ralph Francescone3, Yinfei Tan6, Emmanuelle Nicolas5, Neelima Shah3, Elizabeth A Handorf2, Kathy Q Cai6, Alana M O'Reilly5, Ido Sloma7, Rachel Chiaverelli7, Richard A Moffitt8, Vladimir Khazak9, Carolyn Y Fang10, Erica A Golemis5, Edna Cukierman3, Igor Astsaturov11.
Abstract
Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by KrasG12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.Entities:
Keywords: TGF-β signaling; cholesterol metabolism; epithelial-to-mesenchymal transition; pancreatic cancer
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Year: 2020 PMID： 32976774 PMCID： PMC7572882 DOI： 10.1016/j.ccell.2020.08.015
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743