SOAT1 promotes mevalonate pathway dependency in pancreatic cancer.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
07 09 2020
07 09 2020
Historique:
received:
21
12
2019
revised:
28
03
2020
accepted:
12
05
2020
entrez:
8
7
2020
pubmed:
8
7
2020
medline:
3
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32633781
pii: 151922
doi: 10.1084/jem.20192389
pmc: PMC7478739
pii:
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
Cholesterol
97C5T2UQ7J
Sterol O-Acyltransferase
EC 2.3.1.26
sterol O-acyltransferase 1
EC 2.3.1.26
Mevalonic Acid
S5UOB36OCZ
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : T32 CA160001
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188134
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190092
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211506
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA224013
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA229699
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA087497
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA013106
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA148056
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA210240
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA180717
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA192904
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA226037
Pays : United States
Informations de copyright
© 2020 Oni et al.
Déclaration de conflit d'intérêts
Disclosures: C. Vakoc reported personal fees from KSQ Therapeutics outside the submitted work. D.A. Tuveson reported "other" from Leap Therapeutics, Surface Oncology, and Cygnal Therapeutics; grants from ONO and Fibrogen; and personal fees from Merck outside the submitted work. D.A. Tuveson is a SAB member and stock holder of Leap Therapeutics, Surface Oncology, and Cygnal, has a research project with ONO and Fibrogen, and is a consultant for Merck. None of this work related to the publication. No other disclosures were reported.
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