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

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

Cancer Biology, MetabolismNicholas Liao2020-10 (Oct)