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

A Corrigendum to this article was published on 06 December 2016

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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 CD45C-KITlow/+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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Figure 1: Analysis of protein expression in circulating exosomes from subjects with melanoma.
Figure 2: Role of tumor-derived exosomes in metastasis.
Figure 3: Role of tumor-derived exosomes in bone marrow cell education and metastasis.
Figure 4: MET analysis in tumor and bone marrow cells.
Figure 5: Disrupting Rab27a expression reduces exosome release, tumor growth and metastasis.

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Change history

  • 05 October 2016

    In the version of this article initially published, the upper and middle panels on the left-hand side in Figure 4a were interchanged, and the GAPDH loading panel in Supplementary Figure 6 was incorrect owing to an error in assembling the figures. The original western blot was rescanned to generate the correct GAPDH loading panel for Supplementary Figure 6. A new western blot was scanned to generate the bottom panel on the lefthand side in Figure 4a because the authors could not find the original western blot of the GAPDH loading panel. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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.).

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H.P. developed the hypothesis, designed the experimental approach, performed the experimental work, analyzed the data, coordinated the project and wrote the manuscript. S.L. conducted experimental work. I.M. performed flow cytometry studies and analysis. B.C.-S. conducted mouse work and proteomic characterization of exosomes. G.M.-B. conducted gene expression studies and analysis of microarray data. M.H.-R. conducted mouse work and bone marrow education studies. C.W. conducted mouse work and human studies. G.G.-S. developed bone marrow education assays. A.N.-H. and K.B. quantified exosomes in human plasma. M.A., B.A.G. and Y.K. performed mass spectrometry studies and contributed to data interpretation. C.H. obtained human blood specimens. M.K.C. and J.Y. contributed to the characterization of human plasma exosomes. J.S., R.N.K., V.R.M., M.S.B., J.D.W., P.B.C. and C.M.G. discussed the hypothesis and contributed to data interpretation and experimental design. J.B. coordinated the project, interpreted data and wrote the manuscript. D.L. conceived the hypothesis, led the project, interpreted the data and wrote the manuscript.

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Correspondence to Jacqueline Bromberg or David Lyden.

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Competing interests

J.S. is an inventor on patent applications using microvesicle nucleic acid for diagnostics, which has been licensed to Exosome Diagnostics, Inc. He holds equity in and is an employee of that company.

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Peinado, H., Alečković, M., Lavotshkin, S. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18, 883–891 (2012). https://doi.org/10.1038/nm.2753

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