SOAT1 promotes mevalonate pathway dependency in pancreatic cancer

Oni, T. E., Biffi, G., Baker, L. A., Hao, Y., Tonelli, C., Somerville, T. D. D., Deschênes, A., Belleau, P., Hwang, C. I., Sánchez-Rivera, F. J., Cox, H., Brosnan, E., Doshi, A., Lumia, R. P., Khaledi, K., Park, Y., Trotman, L. C., Lowe, S. W., Krasnitz, A., Vakoc, C. R., Tuveson, D. A. (July 2020) SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. J Exp Med, 217 (9). ISSN 0022-1007

URL: https://pubmed.ncbi.nlm.nih.gov/32633781/

DOI: 10.1084/jem.20192389

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH). In contrast, pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss, indicating a potential therapeutic window for inhibiting SOAT1 in PDAC.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer organism description > animal > mammal > rodent diseases & disorders > cancer > cancer types
CSHL Authors:	Tuveson, David A. Trotman, Lloyd C. Krasnitz, Alexander Lowe, Scott W. Vakoc, Christopher R. Oni, Tobiloba Biffi, Giulia Baker, Lindsey Hao, Yuan Tonelli, Claudia Somerville, Timothy Deschenes, Astrid Belleau, Pascal Hwang, Chang-Il Cox, Hilary Brosnan, Erin Park, Youngkyu Doshi, Abhishek Lumia, Rebecca P Khaledi, Kimia
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Lowe lab CSHL labs > Trotman lab CSHL labs > Tuveson lab CSHL labs > Vakoc lab
Depositing User:	Matthew Dunn
Date:	7 July 2020
Date Deposited:	30 Nov 2020 16:57
Last Modified:	01 Feb 2024 16:39
PMCID:	PMC7478739
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39763

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