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EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming

Author

Listed:
  • Fanyan Meng

    (Wayne State University School of Medicine
    Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University)

  • Ling Wu

    (Wayne State University School of Medicine)

  • Lun Dong

    (Wayne State University School of Medicine
    Shandong University)

  • Allison V. Mitchell

    (Wayne State University School of Medicine)

  • C. James Block

    (Wayne State University School of Medicine)

  • Jenney Liu

    (Wayne State University)

  • Haijun Zhang

    (Huaibei Normal University)

  • Qing Lu

    (Shanghai Jiaotong University)

  • Won-min Song

    (Icahn Mount Sinai School of Medicine)

  • Bin Zhang

    (Icahn Mount Sinai School of Medicine)

  • Wei Chen

    (Wayne State University School of Medicine)

  • Jiani Hu

    (Wayne State University MRI Core)

  • Jian Wang

    (Wayne State University)

  • Qifeng Yang

    (Shandong University)

  • Maik Hüttemann

    (Wayne State University)

  • Guojun Wu

    (Wayne State University School of Medicine)

Abstract

The molecular mechanisms driving metastatic progression in triple-negative breast cancer (TNBC) patients are poorly understood. In this study, we demonstrate that epidermal growth factor-like 9 (EGFL9) is significantly upregulated in basal-like breast cancer cells and associated with metastatic progression in breast tumor samples. Functionally, EGFL9 is both necessary and sufficient to enhance cancer cell migration and invasion, as well as distant metastasis. Mechanistically, we demonstrate that EGFL9 binds cMET, activating cMET-mediated downstream signaling. EGFL9 and cMET co-localize at both the cell membrane and within the mitochondria. We further identify an interaction between EGFL9 and the cytochrome c oxidase (COX) assembly factor COA3. Consequently, EGFL9 regulates COX activity and modulates cell metabolism, promoting a Warburg-like metabolic phenotype. Finally, we show that combined pharmacological inhibition of cMET and glycolysis reverses EGFL9-driven stemness. Our results identify EGFL9 as a therapeutic target for combating metastatic progression in TNBC.

Suggested Citation

  • Fanyan Meng & Ling Wu & Lun Dong & Allison V. Mitchell & C. James Block & Jenney Liu & Haijun Zhang & Qing Lu & Won-min Song & Bin Zhang & Wei Chen & Jiani Hu & Jian Wang & Qifeng Yang & Maik Hütteman, 2019. "EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13034-3
    DOI: 10.1038/s41467-019-13034-3
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