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
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: |
|
| URI: |
https://repository.cshl.edu/id/eprint/39763 |
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