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

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 Hüttemann and Guojun Wu ()
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Fanyan Meng: Wayne State University School of Medicine
Ling Wu: Wayne State University School of Medicine
Lun Dong: Wayne State University School of Medicine
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

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13034-3

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