MYCN-Driven Fatty Acid Uptake Is a Metabolic Vulnerability in Neuroblastoma

Authors

Ling Tao
Mahmoud A Mohammad
Giorgio Milazzo
Myrthala Moreno-Smith
Tajhal D Patel
Barry Zorman
Andrew Badachhape
Blanca E Hernandez
Amber B Wolf
Zihua Zeng
Jennifer H Foster
Sara Aloisi
Pavel Sumazin
Youli Zu
John Hicks
Ketan B Ghaghada
Nagireddy Putluri
Giovanni Perini
Cristian Coarfa
Eveline Barbieri

Publication Date

6-28-2022

Journal

Nature Communications

DOI

10.1038/s41467-022-31331-2

PMID

35764645

PMCID

PMC9240069

PubMedCentral® Posted Date

6-28-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Cell Line, Tumor, Fatty Acids, N-Myc Proto-Oncogene Protein, Neuroblastoma, Cancer metabolism, Targeted therapies, Paediatric cancer

Abstract

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.

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