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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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  • 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.

References

  1. Théry, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2, 569–579 (2002).

    Article  PubMed  Google Scholar 

  2. Iero, M. et al. Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ. 15, 80–88 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Ratajczak, J., Wysoczynski, M., Hayek, F., Janowska-Wieczorek, A. & Ratajczak, M.Z. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20, 1487–1495 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Cocucci, E., Racchetti, G. & Meldolesi, J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 19, 43–51 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. van Niel, G., Porto-Carreiro, I., Simoes, S. & Raposo, G. Exosomes: a common pathway for a specialized function. J. Biochem. 140, 13–21 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Peinado, H., Lavotshkin, S. & Lyden, D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin. Cancer Biol. 21, 139–146 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Ratajczak, J. et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20, 847–856 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Nazarenko, I. et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 70, 1668–1678 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Webber, J., Steadman, R., Mason, M.D., Tabi, Z. & Clayton, A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 70, 9621–9630 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Liu, Y. et al. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am. J. Pathol. 176, 2490–2499 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xiang, X. et al. Induction of myeloid-derived suppressor cells by tumor exosomes. Int. J. Cancer 124, 2621–2633 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Al-Nedawi, K. et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 10, 619–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Hao, S. et al. Epigenetic transfer of metastatic activity by uptake of highly metastatic B16 melanoma cell-released exosomes. Exp. Oncol. 28, 126–131 (2006).

    CAS  PubMed  Google Scholar 

  15. Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sethi, N. & Kang, Y. Unravelling the complexity of metastasis—molecular understanding and targeted therapies. Nat. Rev. Cancer 11, 735–748 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kaplan, R.N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao, D. et al. Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression. Biochim. Biophys. Acta 1796, 33–40 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Erler, J.T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biol. 8, 1369–1375 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Hood, J.L., San, R.S. & Wickline, S.A. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71, 3792–3801 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Jung, T. et al. CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11, 1093–1105 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Trusolino, L., Bertotti, A. & Comoglio, P.M. MET signalling: principles and functions in development, organ regeneration and cancer. Nat. Rev. Mol. Cell Biol. 11, 834–848 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Stella, G.M., Benvenuti, S. & Comoglio, P.M. Targeting the MET oncogene in cancer and metastases. Expert Opin. Investig. Drugs 19, 1381–1394 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Boccaccio, C. & Comoglio, P.M. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat. Rev. Cancer 6, 637–645 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Cecchi, F., Rabe, D.C. & Bottaro, D.P. Targeting the HGF/Met signalling pathway in cancer. Eur. J. Cancer 46, 1260–1270 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Peruzzi, B. & Bottaro, D.P. Targeting the c-Met signaling pathway in cancer. Clin. Cancer Res. 12, 3657–3660 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G.F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Stenmark, H. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10, 513–525 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Ostrowski, M. et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19–30 (2009).

    Article  PubMed  Google Scholar 

  32. Braeuer, R.R., Zigler, M., Villares, G.J., Dobroff, A.S. & Bar-Eli, M. Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment. Semin. Cancer Biol. 21, 83–88 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Fidler, I.J. Critical determinants of melanoma metastasis. J. Investig. Dermatol. Symp. Proc. 1, 203–208 (1996).

    CAS  PubMed  Google Scholar 

  34. Grammatikakis, N. et al. The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation. J. Biol. Chem. 277, 8312–8320 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Fidler, I.J. & Nicolson, G.L. Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. J. Natl. Cancer Inst. 57, 1199–1202 (1976).

    Article  CAS  PubMed  Google Scholar 

  36. Huang, Y. et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 69, 7529–7537 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Hiratsuka, S. et al. The S100A8-serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 10, 1349–1355 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Lucas, R., Verin, A.D., Black, S.M. & Catravas, J.D. Regulators of endothelial and epithelial barrier integrity and function in acute lung injury. Biochem. Pharmacol. 77, 1763–1772 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Joyce, J.A. & Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Balaj, L. et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2, 180 (2011).

    Article  PubMed  Google Scholar 

  41. Taylor, D.D., Taylor, C.G., Jiang, C.G. & Black, P.H. Characterization of plasma membrane shedding from murine melanoma cells. Int. J. Cancer 41, 629–635 (1988).

    Article  CAS  PubMed  Google Scholar 

  42. Zöller, M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat. Rev. Cancer 11, 254–267 (2011).

    Article  PubMed  Google Scholar 

  43. Jalili, A., Shirvaikar, N., Marquez-Curtis, L.A., Turner, A.R. & Janowska-Wieczorek, A. The HGF/c-Met axis synergizes with G-CSF in the mobilization of hematopoietic stem/progenitor cells. Stem Cells Dev. 19, 1143–1151 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Tesio, M. et al. Enhanced c-Met activity promotes G-CSF–induced mobilization of hematopoietic progenitor cells via ROS signaling. Blood 117, 419–428 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Lima, L.G., Chammas, R., Monteiro, R.Q., Moreira, M.E. & Barcinski, M.A. Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner. Cancer Lett. 283, 168–175 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Logozzi, M. et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS ONE 4, e5219 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Guise, T. Examining the metastatic niche: targeting the microenvironment. Semin. Oncol. 37 (suppl. 2), S2–S14 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Aliotta, J.M. et al. Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Exp. Hematol. 38, 233–245 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Aliotta, J.M. et al. Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: a novel mechanism for phenotype modulation. Stem Cells 25, 2245–2256 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Oskarsson, T. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 17, 867–874 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Psaila, B., Kaplan, R.N., Port, E.R. & Lyden, D. Priming the 'soil' for breast cancer metastasis: the pre-metastatic niche. Breast Dis. 26, 65–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Ewing, J. Neoplastic Diseases: A Treatise on Tumours, 3rd edn. (W.B. Saunders Co., Philadelphia, 1928).

  53. Paget, G. The distribution of secondary growths in cancer of the breast. Lancet 133, 571–573 (1889).

    Article  Google Scholar 

  54. Scott, K.L. et al. Proinvasion metastasis drivers in early-stage melanoma are oncogenes. Cancer Cell 20, 92–103 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Christensen, J.G., Burrows, J. & Salgia, R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 225, 1–26 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Akavia, U.D. et al. An integrated approach to uncover drivers of cancer. Cell 143, 1005–1017 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang, J.S., Wang, F.B., Zhang, Q.G., Shen, Z.Z. & Shao, Z.M. Enhanced expression of Rab27A gene by breast cancer cells promoting invasiveness and the metastasis potential by secretion of insulin-like growth factor-II. Mol. Cancer Res. 6, 372–382 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Hendrix, A. et al. Effect of the secretory small GTPase Rab27B on breast cancer growth, invasion, and metastasis. J. Natl. Cancer Inst. 102, 866–880 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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