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

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 and Eveline Barbieri ()
Additional contact information
Ling Tao: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
Mahmoud A. Mohammad: Baylor College of Medicine
Giorgio Milazzo: University of Bologna
Myrthala Moreno-Smith: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
Tajhal D. Patel: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
Barry Zorman: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
Andrew Badachhape: Texas Children’s Hospital, Baylor College of Medicine
Blanca E. Hernandez: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
Amber B. Wolf: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
Zihua Zeng: Houston Methodist Hospital
Jennifer H. Foster: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
Sara Aloisi: University of Bologna
Pavel Sumazin: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
Youli Zu: Houston Methodist Hospital
John Hicks: Baylor College of Medicine
Ketan B. Ghaghada: Texas Children’s Hospital, Baylor College of Medicine
Nagireddy Putluri: Baylor College of Medicine
Giovanni Perini: University of Bologna
Cristian Coarfa: Baylor College of Medicine
Eveline Barbieri: Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31331-2

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