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

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 permane...

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Detalles Bibliográficos
Autores: Peinado, Héctor, Alečković, Maša, Lavotshkin, Simon, Matei, Irina, Costa-Silva, Bruno, Moreno-Bueno, Gema, Hergueta-Redondo, Marta, Williams, Caitlin, García-Santos, Guillermo, Ghajar, Cyrus, Nitadori-Hoshino, Ayuko, Hoffman, Caitlin, Badal, Karen, Garcia, Benjamin A, Callahan, Margaret K, Yuan, Jianda, Martins, Vilma R, Skog, Johan, Kaplan, Rosandra N, Brady, Mary S, Wolchok, Jedd D, Chapman, Paul B, Kang, Yibin, Bromberg, Jacqueline, Lyden, David
Tipo de recurso: artículo
Fecha de publicación:2012
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17965
Acceso en línea:http://hdl.handle.net/20.500.12105/17965
Access Level:acceso abierto
Palabra clave:Animals
Bone Marrow Cells
Cell Line
Exosomes
Female
Humans
Melanoma
Mice
Mice, Inbred C57BL
Phenotype
Prognosis
Proto-Oncogene Proteins c-met
Stem Cells
rab GTP-Binding Proteins
rab27 GTP-Binding Proteins
Descripción
Sumario: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.

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