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Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer.

Cancer cell (2020-09-26)
Linara Gabitova-Cornell, Aizhan Surumbayeva, Suraj Peri, Janusz Franco-Barraza, Diana Restifo, Nicole Weitz, Charline Ogier, Aaron R Goldman, Tiffiney R Hartman, Ralph Francescone, Yinfei Tan, Emmanuelle Nicolas, Neelima Shah, Elizabeth A Handorf, Kathy Q Cai, Alana M O'Reilly, Ido Sloma, Rachel Chiaverelli, Richard A Moffitt, Vladimir Khazak, Carolyn Y Fang, Erica A Golemis, Edna Cukierman, Igor Astsaturov
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Atorvastatin Calcium, Pharmaceutical Secondary Standard; Certified Reference Material
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Transforming Growth Factor-β1 human, TGF-β1, recombinant, expressed in CHO cells, powder, suitable for cell culture
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Puromycin dihydrochloride from Streptomyces alboniger, powder, BioReagent, suitable for cell culture
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Caerulein, ≥95% (HPLC)
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Anti-TGFBR2 antibody produced in rabbit, IgG fraction of antiserum
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Rifapentine