MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 06 2022
28 06 2022
Historique:
received:
24
08
2021
accepted:
07
06
2022
entrez:
28
6
2022
pubmed:
29
6
2022
medline:
1
7
2022
Statut:
epublish
Résumé
Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.
Identifiants
pubmed: 35764645
doi: 10.1038/s41467-022-31331-2
pii: 10.1038/s41467-022-31331-2
pmc: PMC9240069
doi:
Substances chimiques
Fatty Acids
0
N-Myc Proto-Oncogene Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3728Subventions
Organisme : NCI NIH HHS
ID : R01 CA224304
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222224
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES030285
Pays : United States
Organisme : NIDCR NIH HHS
ID : U01 DE028233
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220297
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES027725
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216426
Pays : United States
Informations de copyright
© 2022. The Author(s).
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