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Cancer Cell Derived Small Extracellular Vesicles Contribute to Recipient Cell Metastasis Through Promoting HGF/c-Met Pathway*,

https://doi.org/10.1074/mcp.RA119.001502Get rights and content
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Cancer progression is frequently caused by metastasis and leads to significantly increased mortality. Cell derived extracellular vesicles, including exosomes, in the microenvironment play key roles in cellular signal transduction, whereas their biological function in cancer metastasis and progression needs in-depth investigation. Here, we initially demonstrate that the small extracellular vesicles (sEVs) derived from highly metastatic lung cancer cells exhibited great capacity to promote the progression of recipient cells. Quantitative proteomics was employed to comprehensively decipher the proteome of cell derived sEVs and more than 1400 sEVs proteins were identified. Comparison analysis indicates that sEVs-HGF is a potential metastasis related protein and our verification data from clinical lung cancer plasma samples and in vivo experiments further confirmed the association. We found that sEVs-HGF could induce epithelial-mesenchymal transition and the coordination between HGF and c-Met was confirmed through corresponding target knockdown and kinase inhibition. Our data collectively demonstrate that cancer cell derived sEVs contribute to recipient cell metastasis through promoting HGF/c-Met pathway, which are potential targets for the prevention and treatment of cancer metastasis.

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Highlights

  • Quantitative proteomics analysis of cancer cell derived small extracellular vesicles (sEVs) reveals metastasis related proteins.

  • HGF/c-Met signaling pathway is mainly activated by cancer cell-secreted sEVs-HGF.

  • sEVs-HGF plays essential role in the metastasis of cancer cells.

Exosomes
Lung cancer
Metastasis
Mass Spectrometry
Subcellular analysis
HGF/c-Met pathway
Proteomics

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Author contributions: Z.Q., Y.Z., M.G., and H.X. designed research; Z.Q., Y.Z., M.G., and H.X. performed research; Z.Q., Y.Z., M.G., and H.X. contributed new reagents/analytic tools; Z.Q., Y.Z., M.G., S.L., X.J., Z.S., H.L., C.C., and H.X. analyzed data; Z.Q., Y.Z., M.G., and H.X. wrote the paper.

*

This work was supported by grants from the National Key Research and Development Program (No. 2017YFC1200204), the National Natural Science Foundation of China (No. 21675110, No. 21475086, No. 21305087), the Committee of Shanghai Science and Technology (No. 14DZ0501200 and No. 15142200300), and the Key Scientific Project of Shanghai Jiao Tong University (No. YG2014QN21, YG2015MS48 and YG2017MS80). H.X. is supported by the Recruitment Program of Global Youth Experts of China and National High-tech R&D Program of China (863 Program, No. 2014AA020545).

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This article contains supplemental Figures and Tables. The authors declare no competing financial interests

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These authors contributed equally as first authors to this work.