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

Author

Listed:
  • Ling Tao

    (Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
    Baylor College of Medicine)

  • Mahmoud A. Mohammad

    (Baylor College of Medicine
    National Research Centre)

  • Giorgio Milazzo

    (University of Bologna)

  • Myrthala Moreno-Smith

    (Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
    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
    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
    Baylor College of Medicine)

  • Amber B. Wolf

    (Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
    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
    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
    Baylor College of Medicine
    Baylor College of Medicine)

  • Giovanni Perini

    (University of Bologna)

  • Cristian Coarfa

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Eveline Barbieri

    (Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine
    Baylor College of Medicine)

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.

Suggested Citation

  • 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 & , 2022. "MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31331-2
    DOI: 10.1038/s41467-022-31331-2
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