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

Fanyan Meng,Qifeng Yang,Lun Dong,Guojun Wu,Jian Wang,Qing Lu,Bin Zhang,Haijun Zhang,Maik Hüttemann,Jenney Liu,Jiani Hu,C James Block,Ling Wu,Allison V Mitchell,Wei Chen,Won-Min Song

doi:10.1038/s41467-019-13034-3

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.

Highlights

The molecular mechanisms driving metastatic progression in triple-negative breast cancer (TNBC) patients are poorly understood
Our results showed that only epidermal growth factor-like 9 (EGFL9) was preferentially expressed in basal-like breast cancer cells
We found that the activity of c oxidase (COX) was decreased by 54.5% in the EGFL9 overexpression cell model compared to LacZ control (Fig. 7c), indicating that the electron transport chain (ETC) was targeted by EGFL9 signaling

Summary

Introduction

The molecular mechanisms driving metastatic progression in triple-negative breast cancer (TNBC) patients are poorly understood. 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. Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, 4100 John R, Detroit, MI 48201, USA. In addition to genetic mutations, altered gene expression, and aberrant activation of critical signaling pathways, cancer cells exhibit apparent mitochondrial dysfunction during cancer progression and metastasis. EGF and Epiregulin (a member of the EGF family) can function as a ligand of epidermal growth factor receptor (EGFR) and activate EGFR signaling, which will promote multiple biological consequences associated with cancer development. Our results suggest that high expression of EGFL9 and its induction of both cMET signaling activation and metabolic reprogramming is a novel mechanism promoting breast cancer metastasis. We propose EGFL9 signaling as a therapeutic target for developing an effective treatment for metastatic breast cancer

Methods

Results

Conclusion