Abstract C06: Cholesterol deprivation induces TGFβ signaling to promote basal differentiation in pancreatic cancer

Abstract

Oncogenic transformation alters the metabolism of cellular nutrients to sustain tumor growth. We here define a mechanism by which modifications in cholesterol metabolism control the formation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by means of conditional inactivation of Nsdhl in mice bearing a tumor-inducing Kras mutation (KrasG12D) prevented PDAC formation in the context of a heterozygous Trp53f/+ genotype without impairing normal pancreatic development. In mice with pancreatic Nsdhl ablation and homozygous loss of Trp53, the emerging tumors presented with the aggressive basal (mesenchymal) phenotype as opposed to the classic (glandular) PDAC. This paralleled significantly reduced expression of cholesterol metabolic pathway genes in human basal PDAC subtype. Mechanistically, we demonstrate that genetic or metabolic reduction in cellular cholesterol induces the expression of transforming growth factor beta (TGF) and activates pro-mesenchymal effectors in human and murine PDAC, providing a direct transcriptional mechanism by which cholesterol metabolism can condition tumor differentiation. Activity of TGF beta pathway estimated via pSMAD2 expression in surgical PDAC samples inversely correlated with patients’ blood cholesterol levels, especially in patients taking cholesterol-lowering statins. Conclusions: Low levels of cellular cholesterol induce autocrine TGF beta signaling in PDAC. Malnutrition or cholesterol-lowering statins may be mechanistically linked to basal PDAC differentiation. Citation Format: Linara Gabitova, Suraj Peri, Ralph Francescone, Janusz Franco-Barraza, Neelima Shah, Emmanuelle Nicolas, Elizabeth A. Handorf, Kathy Q. Cai, Ido Sloma, Rachel Chiaverelli, Richard Moffitt, Erica A. Golemis, Carolyn Fang, Shannon Lynch, Edna Cukierman, Igor Astsaturov. Cholesterol deprivation induces TGFβ signaling to promote basal differentiation in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C06.