TY - JOUR
T1 - Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET
AU - Peinado, Héctor
AU - Alečković, Maša
AU - Lavotshkin, Simon
AU - Matei, Irina
AU - Costa-Silva, Bruno
AU - Moreno-Bueno, Gema
AU - Hergueta-Redondo, Marta
AU - Williams, Caitlin
AU - García-Santos, Guillermo
AU - Ghajar, Cyrus M.
AU - Nitadori-Hoshino, Ayuko
AU - Hoffman, Caitlin
AU - Badal, Karen
AU - Garcia, Benjamin A.
AU - Callahan, Margaret K.
AU - Yuan, Jianda
AU - Martins, Vilma R.
AU - Skog, Johan
AU - Kaplan, Rosandra N.
AU - Brady, Mary S.
AU - Wolchok, Jedd D.
AU - Chapman, Paul B.
AU - Kang, Yibin
AU - Bromberg, Jacqueline
AU - Lyden, David
N1 - Funding Information:
We dedicate this work to the memory of James A. Paduano. We thank M.J. Bissell, A. Cano, J. Wels and S.R. Granitto for critical reading of this paper and suggestions. We also thank the members of our laboratories for helpful discussions and the members of the Weill Cornell Medical College electron microscopy and microarray core facilities for their support. We thank V. Hearing, (US National Institutes of Health (NIH), National Cancer Institute (NCI)) for providing the antibody to TYRP2 and D.C. Bennett (St. George’s University of London) for providing the melan-a cell line. Our work is supported by grants from the Children’s Cancer and Blood Foundation (H.P. and D.L.), The Manning Foundation (B.C.-S. and D.L.), The Hartwell Foundation (D.L.), Pediatric Oncology Experimental Therapeutics Investigators Consortium (H.P. and D.L.), Stavros S. Niarchos Foundation (D.L.), Champalimaud Foundation (H.P., Y.K. and D.L.), The Nancy C. and Daniel P. Paduano Foundation (H.P. and D.L.), The Mary Kay Foundation (A.N.-H. and D.L.), American Hellenic Educational Progressive Association 5th District (D.L.), The Malcolm Hewitt Wiener Foundation (D.L.), The George Best Costacos Foundation (D.L.), NCI (D.L., grant NCI-R01CA 098234-01), National Foundation for Cancer Research (D.L.), Susan G. Komen for the Cure (H.P. and D.L.), NCI-U54-CA143836 training grant (C.M.G. and D.L.), Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología (G.G.-S.), Fundación Universidad de Oviedo (G.G.-S.), The Beth C. Tortolani Foundation (H.P., D.L. and J.B.), Sussman Family Fund (J.B.), Charles and Marjorie Holloway Foundation (J.B.), Manhassat Breast Cancer Fund (J.B.), NIH-CA87637 (J.B.), Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, V.R.M. and B.C.-S.), NIH (Y.K., grants R01-CA134519 and R01-CA141062), National Science Foundation grant CBET-0941143 and an American Society for Mass Spectrometry research award (B.A.G.).
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862007577&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862007577&partnerID=8YFLogxK
U2 - 10.1038/nm.2753
DO - 10.1038/nm.2753
M3 - Article
C2 - 22635005
AN - SCOPUS:84862007577
SN - 1078-8956
VL - 18
SP - 883
EP - 891
JO - Nature Medicine
JF - Nature Medicine
IS - 6
ER -