Cancer Cell. 2020 Oct 12;38(4):567-583.e11. doi: 10.1016/j.ccell.2020.08.015. | PubMed

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

1. Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA; The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
2. Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA.
3. The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA; Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
4. Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA, USA.
5. Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
6. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
7. Champions Oncology, Inc., Hackensack, NJ, USA.
8. Department of Biomedical Informatics, Stony Brook Cancer Center, Stony Brook, NY, USA.
9. NexusPharma, Inc., Philadelphia, PA, USA.
10. Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
11. Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA; The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA; Kazan Federal University, Kazan, Russian Federation. Electronic address: igor.astsaturov@fccc.edu.

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.

Presented By Linara Gabitova | ORCID iD