MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Authors: TAO, LING - Baylor College Of Medicine; MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC); MILAZZO, GIORGIO - Bologna University Hospital Authority St Orsola-Malpighi Polyclinic; MORENO-SMITH, MYRTHALA - Baylor College Of Medicine; PATEL, TAJHAL - Baylor College Of Medicine; ZORMAN, BARRY - Baylor College Of Medicine; BADACHHAPE, ANDREW - Baylor College Of Medicine; HERNANDEZ, BLANCA - Baylor College Of Medicine; WOLF, AMBER - Baylor College Of Medicine; ZENG, ZIHUA - Methodist Hospital; FOSTER, JENNIFER - Texas Children'S Hospital; ALOISI, SARA - Bologna University Hospital Authority St Orsola-Malpighi Polyclinic; SUMAZIN, PAVEL - Texas Children'S Hospital; ZU, YOULI - Methodist Hospital; HICKS, JOHN - Baylor College Of Medicine; GHAGHADA, KETAN - Texas Children'S Hospital; PUTLURI, NAGIREDDY - Baylor College Of Medicine; PERINI, GIOVANNI - Bologna University Hospital Authority St Orsola-Malpighi Polyclinic; COARFA, CRISTIAN - Baylor College Of Medicine; BARBIERI, EVELINE - Texas Children'S Hospital

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/7/2022
Publication Date: 6/28/2022
Citation: Tao, L., Mohammad, M.A., Milazzo, G., Moreno-Smith, M., Patel, T.D., Zorman, B., Badachhape, A., Hernandez, B.E., Wolf, A.B., Zeng, Z., Foster, J.H., Aloisi, S., Sumazin, P., Zu, Y., Hicks, J., Ghaghada, K.B., Putluri, N., Perini, G., Coarfa, C., Barbieri, E. 2022. MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma. Nature Communications. 13: Article 3728. https://doi.org/10.1038/s41467-022-31331-2.
DOI: https://doi.org/10.1038/s41467-022-31331-2

Interpretive Summary: Nerolastoma (NB) is a type of cancer that affects children and starts in certain nerve cells. In some cases of high-risk NB, there is a gene called MYCN that becomes more active, but there are no treatments that directly target this gene. In this study, researchers looked at the way MYCN affects the metabolism (how the body uses energy) in NB cells. The study showed that when MYCN is active, it causes the cells to accumulate certain fats called glycerolipids by increasing the uptake and production of fatty acids (FAs). These NB cells become dependent on getting FAs from their surroundings to survive. Additionally, the research revealed that MYCN directly boosts the production of a protein called FATP2, which helps the cells take in FAs. When this protein was stopped, either by taking it out genetically or using drugs to block it, it was discovered that it made it harder for NB cells to survive and slowed down the growth of tumors, helped animals live longer, and worked even better when used alongside traditional cancer treatments in experiments with NB. Our findings show that NB cells with active MYCN rely heavily on taking in fatty acids and blocking this process could be a promising way to improve current treatments for this type of cancer.

Technical 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.