Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
J Exp Med ; 217(9)2020 09 07.
Article in English | MEDLINE | ID: mdl-32633781

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.


Subject(s)
Mevalonic Acid/metabolism , Pancreatic Neoplasms/enzymology , Sterol O-Acyltransferase/metabolism , Animals , Cell Line, Tumor , Cholesterol/metabolism , Disease Progression , Humans , Loss of Heterozygosity/genetics , Mice, Inbred C57BL , Models, Biological , Pancreatic Neoplasms/pathology , Sterol O-Acyltransferase/deficiency , Tumor Suppressor Protein p53/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...