EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming
| Autor: | Qing Lu, Fanyan Meng, Jenney Liu, Jian Wang, Guojun Wu, C. James Block, Qifeng Yang, Won-Min Song, Wei Chen, Allison V. Mitchell, Jiani Hu, Ling Wu, Bin Zhang, Maik Hüttemann, Lun Dong, Haijun Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
General Physics and Astronomy Triple Negative Breast Neoplasms Mitochondrion Metastasis Breast cancer 0302 clinical medicine Cell Movement Neoplasm Metastasis skin and connective tissue diseases lcsh:Science Membrane Potential Mitochondrial Regulation of gene expression Multidisciplinary Proto-Oncogene Proteins c-met 3. Good health Gene Expression Regulation Neoplastic Gene Knockdown Techniques 030220 oncology & carcinogenesis Female Signal transduction Glycolysis Signal Transduction Science Breast Neoplasms Article General Biochemistry Genetics and Molecular Biology Electron Transport Complex IV Mitochondrial Proteins 03 medical and health sciences Downregulation and upregulation Cell Line Tumor medicine Humans Cell Proliferation Epidermal Growth Factor Cell growth business.industry Membrane Proteins General Chemistry medicine.disease Glucose 030104 developmental biology Cell culture Cancer research lcsh:Q business |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-13034-3 |
| Popis: | 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. Triple-negative breast cancer is an aggressive form of the disease. Here, the authors identify EGFL9 as a mediator of metastasis in TNBC through interactions with cMET. |
| Databáze: | OpenAIRE |
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