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. (September 2020) SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. J Exp Med, 217 (9). ISSN 0022-1007

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 > cancer types > pancreatic cancer
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 labs > Lowe lab CSHL labs > Trotman lab CSHL labs > Tuveson lab CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User:	Matthew Dunn
Date:	7 September 2020
Date Deposited:	30 Nov 2020 16:57
Last Modified:	13 Jul 2021 19:56
PMCID:	PMC7478739
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39763

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