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Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion
Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients wi...
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/PMC8938495/ https://www.ncbi.nlm.nih.gov/pubmed/35314680 http://dx.doi.org/10.1038/s41467-022-29137-3 |
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author | Jiang, Nian Xie, Bowen Xiao, Wenwu Fan, Ming Xu, Shanxiu Duan, Yixin Hamsafar, Yamah Evans, Angela C. Huang, Jie Zhou, Weibing Lin, Xuelei Ye, Ningrong Wanggou, Siyi Chen, Wen Jing, Di Fragoso, Ruben C. Dugger, Brittany N. Wilson, Paul F. Coleman, Matthew A. Xia, Shuli Li, Xuejun Sun, Lun-Quan Monjazeb, Arta M. Wang, Aijun Murphy, William J. Kung, Hsing-Jien Lam, Kit S. Chen, Hong-Wu Li, Jian Jian |
author_facet | Jiang, Nian Xie, Bowen Xiao, Wenwu Fan, Ming Xu, Shanxiu Duan, Yixin Hamsafar, Yamah Evans, Angela C. Huang, Jie Zhou, Weibing Lin, Xuelei Ye, Ningrong Wanggou, Siyi Chen, Wen Jing, Di Fragoso, Ruben C. Dugger, Brittany N. Wilson, Paul F. Coleman, Matthew A. Xia, Shuli Li, Xuejun Sun, Lun-Quan Monjazeb, Arta M. Wang, Aijun Murphy, William J. Kung, Hsing-Jien Lam, Kit S. Chen, Hong-Wu Li, Jian Jian |
author_sort | Jiang, Nian |
collection | PubMed |
description | Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A(−/−), CPT2(−/−), ACAD9(−/−) cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy. |
format | Online Article Text |
id | pubmed-8938495 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-89384952022-04-08 Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion Jiang, Nian Xie, Bowen Xiao, Wenwu Fan, Ming Xu, Shanxiu Duan, Yixin Hamsafar, Yamah Evans, Angela C. Huang, Jie Zhou, Weibing Lin, Xuelei Ye, Ningrong Wanggou, Siyi Chen, Wen Jing, Di Fragoso, Ruben C. Dugger, Brittany N. Wilson, Paul F. Coleman, Matthew A. Xia, Shuli Li, Xuejun Sun, Lun-Quan Monjazeb, Arta M. Wang, Aijun Murphy, William J. Kung, Hsing-Jien Lam, Kit S. Chen, Hong-Wu Li, Jian Jian Nat Commun Article Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A(−/−), CPT2(−/−), ACAD9(−/−) cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy. Nature Publishing Group UK 2022-03-21 /pmc/articles/PMC8938495/ /pubmed/35314680 http://dx.doi.org/10.1038/s41467-022-29137-3 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 Jiang, Nian Xie, Bowen Xiao, Wenwu Fan, Ming Xu, Shanxiu Duan, Yixin Hamsafar, Yamah Evans, Angela C. Huang, Jie Zhou, Weibing Lin, Xuelei Ye, Ningrong Wanggou, Siyi Chen, Wen Jing, Di Fragoso, Ruben C. Dugger, Brittany N. Wilson, Paul F. Coleman, Matthew A. Xia, Shuli Li, Xuejun Sun, Lun-Quan Monjazeb, Arta M. Wang, Aijun Murphy, William J. Kung, Hsing-Jien Lam, Kit S. Chen, Hong-Wu Li, Jian Jian Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion |
title | Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion |
title_full | Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion |
title_fullStr | Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion |
title_full_unstemmed | Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion |
title_short | Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion |
title_sort | fatty acid oxidation fuels glioblastoma radioresistance with cd47-mediated immune evasion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938495/ https://www.ncbi.nlm.nih.gov/pubmed/35314680 http://dx.doi.org/10.1038/s41467-022-29137-3 |
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