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Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer
Cancer Cell. 2020 Sep 15;38(4) :567-583 e11
PMID: 32976774    PMCID: PMC7572882    URL: https://www.ncbi.nlm.nih.gov/pubmed/32976774
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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 Kras(G12D) 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.
1878-3686 Gabitova-Cornell, Linara Surumbayeva, Aizhan Peri, Suraj Franco-Barraza, Janusz Restifo, Diana Weitz, Nicole Ogier, Charline Goldman, Aaron R Hartman, Tiffiney R Francescone, Ralph Tan, Yinfei Nicolas, Emmanuelle Shah, Neelima Handorf, Elizabeth A Cai, Kathy Q O'Reilly, Alana M Sloma, Ido Chiaverelli, Rachel Moffitt, Richard A Khazak, Vladimir Fang, Carolyn Y Golemis, Erica A Cukierman, Edna Astsaturov, Igor P30 CA006927/CA/NCI NIH HHS/United States R01 CA232256/CA/NCI NIH HHS/United States R21 CA231252/CA/NCI NIH HHS/United States Journal Article United States Cancer Cell. 2020 Sep 15:S1535-6108(20)30426-8. doi: 10.1016/j.ccell.2020.08.015.