Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

Héctor Peinado, Maša Alečković, Simon Lavotshkin, Irina Matei, Bruno Costa-Silva, Gema Moreno-Bueno, Marta Hergueta-Redondo, Caitlin Williams, Guillermo García-Santos, Cyrus M. Ghajar, Ayuko Nitadori-Hoshino, Caitlin Hoffman, Karen Badal, Benjamin A. Garcia, Margaret K. Callahan, Jianda Yuan, Vilma R. Martins, Johan Skog, Rosandra N. Kaplan, Mary S. BradyJedd D. Wolchok, Paul B. Chapman, Yibin Kang, Jacqueline Bromberg, David Lyden

Research output: Contribution to journalArticle

1832 Scopus citations

Abstract

Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45-C-KIT low/+TIE2 + bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.

Original languageEnglish (US)
Pages (from-to)883-891
Number of pages9
JournalNature Medicine
Volume18
Issue number6
DOIs
StatePublished - Jun 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Peinado, H., Alečković, M., Lavotshkin, S., Matei, I., Costa-Silva, B., Moreno-Bueno, G., Hergueta-Redondo, M., Williams, C., García-Santos, G., Ghajar, C. M., Nitadori-Hoshino, A., Hoffman, C., Badal, K., Garcia, B. A., Callahan, M. K., Yuan, J., Martins, V. R., Skog, J., Kaplan, R. N., ... Lyden, D. (2012). Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine, 18(6), 883-891. https://doi.org/10.1038/nm.2753