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Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion

Author

Listed:
  • Nian Jiang

    (University of California Davis School of Medicine
    Central South University)

  • Bowen Xie

    (University of California Davis School of Medicine
    Tsinghua University)

  • Wenwu Xiao

    (University of California Davis)

  • Ming Fan

    (University of California Davis School of Medicine)

  • Shanxiu Xu

    (University of California Davis)

  • Yixin Duan

    (University of California Davis School of Medicine)

  • Yamah Hamsafar

    (University of California Davis)

  • Angela C. Evans

    (University of California Davis School of Medicine)

  • Jie Huang

    (University of California Davis School of Medicine)

  • Weibing Zhou

    (University of California Davis School of Medicine
    Central South University)

  • Xuelei Lin

    (Central South University)

  • Ningrong Ye

    (Central South University)

  • Siyi Wanggou

    (Central South University)

  • Wen Chen

    (University of California Davis School of Medicine
    Central South University)

  • Di Jing

    (University of California Davis
    Central South University)

  • Ruben C. Fragoso

    (University of California Davis School of Medicine
    University of California Davis)

  • Brittany N. Dugger

    (University of California Davis)

  • Paul F. Wilson

    (University of California Davis School of Medicine
    University of California Davis)

  • Matthew A. Coleman

    (University of California Davis School of Medicine
    University of California Davis)

  • Shuli Xia

    (Johns Hopkins School of Medicine)

  • Xuejun Li

    (Central South University
    Central South University)

  • Lun-Quan Sun

    (Central South University)

  • Arta M. Monjazeb

    (University of California Davis School of Medicine
    University of California Davis)

  • Aijun Wang

    (University of California Davis)

  • William J. Murphy

    (University of California Davis
    UC Davis School of Medicine)

  • Hsing-Jien Kung

    (University of California Davis
    Taipei Medical University)

  • Kit S. Lam

    (University of California Davis
    University of California Davis)

  • Hong-Wu Chen

    (University of California Davis
    University of California Davis
    Veterans Affairs Northern California Health Care System)

  • Jian Jian Li

    (University of California Davis School of Medicine
    University of California Davis)

Abstract

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.

Suggested Citation

  • Nian Jiang & Bowen Xie & Wenwu Xiao & Ming Fan & Shanxiu Xu & Yixin Duan & Yamah Hamsafar & Angela C. Evans & Jie Huang & Weibing Zhou & Xuelei Lin & Ningrong Ye & Siyi Wanggou & Wen Chen & Di Jing & , 2022. "Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29137-3
    DOI: 10.1038/s41467-022-29137-3
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    Cited by:

    1. Ipshita Nandi & Linjia Ji & Harvey W. Smith & Daina Avizonis & Vasilios Papavasiliou & Cynthia Lavoie & Alain Pacis & Sherif Attalla & Virginie Sanguin-Gendreau & William J. Muller, 2024. "Targeting fatty acid oxidation enhances response to HER2-targeted therapy," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Wentao Zhao & Cong Ouyang & Liang Zhang & Jinyang Wang & Jiaojiao Zhang & Yan Zhang & Chen Huang & Qiao Xiao & Bin Jiang & Furong Lin & Cixiong Zhang & Mingxia Zhu & Changchuan Xie & Xi Huang & Bingch, 2024. "The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Chuanyuan Wei & Wei Sun & Kangjie Shen & Jingqin Zhong & Wanlin Liu & Zixu Gao & Yu Xu & Lu Wang & Tu Hu & Ming Ren & Yinlam Li & Yu Zhu & Shaoluan Zheng & Ming Zhu & Rongkui Luo & Yanwen Yang & Yingy, 2023. "Delineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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