MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 28, 2022
- Source ID
- 10.1038/s41467-022-31331-2
Entities
People
- Amber B. Wolf
- Andrew Badachhape
- Barry Zorman
- Blanca E. Hernandez
- Cristian Coarfa
- Eveline Barbieri
- Giorgio Milazzo
- Giovanni Perini
- Jennifer H. Foster
- John Hicks
- Ketan B. Ghaghada
- Ling Tao
- Mahmoud A Mohammad
- Myrthala Moreno-smith
- Nagireddy Putluri
- Pavel Sumazin
- Sara Aloisi
- Tajhal D. Patel
- Youli Zu
- Zihua Zeng
Organizations
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- United States Department of Defense