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

Author

Gabitova-Cornell L, Surumbayeva A, Peri S, Franco-Barraza J, Restifo D, Weitz N, Ogier C, Goldman AR, Hartman TR, Francescone R, Tan Y, Nicolas E, Shah N, Handorf EA, Cai KQ, O'Reilly AM, Sloma I, Chiaverelli R, Moffitt RA, Khazak V, Fang CY, Golemis EA, Cukierman E, and Astsaturov I

Subjects
3-Hydroxysteroid Dehydrogenases genetics, 3-Hydroxysteroid Dehydrogenases metabolism, Animals, Atorvastatin pharmacology, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal metabolism, Cell Differentiation drug effects, Cell Differentiation genetics, Cell Line, Tumor, Epithelial-Mesenchymal Transition drug effects, Epithelial-Mesenchymal Transition genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Kaplan-Meier Estimate, Mice, Inbred C57BL, Mice, Knockout, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, Signal Transduction genetics, Transforming Growth Factor beta metabolism, Xenograft Model Antitumor Assays methods, Biosynthetic Pathways genetics, Carcinoma, Pancreatic Ductal genetics, Cholesterol, LDL biosynthesis, Pancreatic Neoplasms genetics, Transforming Growth Factor beta genetics
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 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., Competing Interests: Declaration of Interests I.A. served as a consultant for Caris Life Sciences, Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Published
2020
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2. Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR.

Author

Gabitova L, Restifo D, Gorin A, Manocha K, Handorf E, Yang DH, Cai KQ, Klein-Szanto AJ, Cunningham D, Kratz LE, Herman GE, Golemis EA, and Astsaturov I

Subjects
3-Hydroxysteroid Dehydrogenases genetics, 3-Hydroxysteroid Dehydrogenases metabolism, Animals, Cell Line, Tumor, ErbB Receptors antagonists & inhibitors, Female, Humans, Liver X Receptors, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Orphan Nuclear Receptors agonists, Papilloma genetics, Papilloma metabolism, Papilloma pathology, Signal Transduction, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology, Transfection, Cholesterol metabolism, ErbB Receptors metabolism, Proto-Oncogene Proteins p21(ras) metabolism, Sterols metabolism
Abstract

Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRAS(G12D). Strikingly, Nsdhl inactivation antagonized the growth of skin tumors while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2015
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