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.

致癌转化改变脂质代谢以维持肿瘤生长。我们定义了胆固醇代谢控制胰腺导管腺癌 (PDAC) 发展和分化的机制。在由Kras ^G12D表达和纯合Trp53缺失驱动的小鼠模型中，通过限速酶Nsdhl的条件失活或用降胆固醇他汀类药物治疗来破坏远端胆固醇生物合成，将腺胰腺癌转变为基底（间充质）表型。一致地，接受他汀类药物治疗的患者的 PDAC 显示出增强的间充质特征。从机制上讲，他汀类药物和 NSDHL 缺失诱导 SREBP1 激活，从而促进Tgfb1的表达，使上皮间质转化成为可能。本研究中来自患者样本的证据表明，通过降低胆固醇的他汀类药物激活转化生长因子 β 信号传导和上皮-间质转化可能会促进 PDAC 的基础类型，从而导致患者预后不佳。