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, Guojun Wu

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish
Article number5033
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

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