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MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma
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 tu...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240069/ https://www.ncbi.nlm.nih.gov/pubmed/35764645 http://dx.doi.org/10.1038/s41467-022-31331-2 |
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author | Tao, Ling Mohammad, Mahmoud A. Milazzo, Giorgio Moreno-Smith, Myrthala Patel, Tajhal D. Zorman, Barry Badachhape, Andrew Hernandez, Blanca E. Wolf, Amber B. Zeng, Zihua Foster, Jennifer H. Aloisi, Sara Sumazin, Pavel Zu, Youli Hicks, John Ghaghada, Ketan B. Putluri, Nagireddy Perini, Giovanni Coarfa, Cristian Barbieri, Eveline |
author_facet | Tao, Ling Mohammad, Mahmoud A. Milazzo, Giorgio Moreno-Smith, Myrthala Patel, Tajhal D. Zorman, Barry Badachhape, Andrew Hernandez, Blanca E. Wolf, Amber B. Zeng, Zihua Foster, Jennifer H. Aloisi, Sara Sumazin, Pavel Zu, Youli Hicks, John Ghaghada, Ketan B. Putluri, Nagireddy Perini, Giovanni Coarfa, Cristian Barbieri, Eveline |
author_sort | Tao, Ling |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9240069 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92400692022-06-30 MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma Tao, Ling Mohammad, Mahmoud A. Milazzo, Giorgio Moreno-Smith, Myrthala Patel, Tajhal D. Zorman, Barry Badachhape, Andrew Hernandez, Blanca E. Wolf, Amber B. Zeng, Zihua Foster, Jennifer H. Aloisi, Sara Sumazin, Pavel Zu, Youli Hicks, John Ghaghada, Ketan B. Putluri, Nagireddy Perini, Giovanni Coarfa, Cristian Barbieri, Eveline Nat Commun Article 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. Nature Publishing Group UK 2022-06-28 /pmc/articles/PMC9240069/ /pubmed/35764645 http://dx.doi.org/10.1038/s41467-022-31331-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Tao, Ling Mohammad, Mahmoud A. Milazzo, Giorgio Moreno-Smith, Myrthala Patel, Tajhal D. Zorman, Barry Badachhape, Andrew Hernandez, Blanca E. Wolf, Amber B. Zeng, Zihua Foster, Jennifer H. Aloisi, Sara Sumazin, Pavel Zu, Youli Hicks, John Ghaghada, Ketan B. Putluri, Nagireddy Perini, Giovanni Coarfa, Cristian Barbieri, Eveline MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma |
title | MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma |
title_full | MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma |
title_fullStr | MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma |
title_full_unstemmed | MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma |
title_short | MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma |
title_sort | mycn-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240069/ https://www.ncbi.nlm.nih.gov/pubmed/35764645 http://dx.doi.org/10.1038/s41467-022-31331-2 |
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