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-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.
At a glance
Gene Expression Omnibus
- Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2, 569–579 (2002). , &
- Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ. 15, 80–88 (2008). et al.
- Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20, 1487–1495 (2006). , , , &
- Shedding microvesicles: artefacts no more. Trends Cell Biol. 19, 43–51 (2009). , &
- Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007). et al.
- Exosomes: a common pathway for a specialized function. J. Biochem. 140, 13–21 (2006). , , &
- The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin. Cancer Biol. 21, 139–146 (2011). , &
- Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20, 847–856 (2006). et al.
- Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 70, 1668–1678 (2010). et al.
- Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 70, 9621–9630 (2010). , , , &
- Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am. J. Pathol. 176, 2490–2499 (2010). et al.
- Induction of myeloid-derived suppressor cells by tumor exosomes. Int. J. Cancer 124, 2621–2633 (2009). et al.
- Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 10, 619–624 (2008). et al.
- Epigenetic transfer of metastatic activity by uptake of highly metastatic B16 melanoma cell-released exosomes. Exp. Oncol. 28, 126–131 (2006). et al.
- Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008). et al.
- Unravelling the complexity of metastasis—molecular understanding and targeted therapies. Nat. Rev. Cancer 11, 735–748 (2011). &
- The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009). &
- VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005). 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). 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). et al.
- Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biol. 8, 1369–1375 (2006). , , &
- Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71, 3792–3801 (2011). , &
- CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11, 1093–1105 (2009). et al.
- MET signalling: principles and functions in development, organ regeneration and cancer. Nat. Rev. Mol. Cell Biol. 11, 834–848 (2010). , &
- Targeting the MET oncogene in cancer and metastases. Expert Opin. Investig. Drugs 19, 1381–1394 (2010). , &
- Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat. Rev. Cancer 6, 637–645 (2006). &
- Targeting the HGF/Met signalling pathway in cancer. Eur. J. Cancer 46, 1260–1270 (2010). , &
- Targeting the c-Met signaling pathway in cancer. Clin. Cancer Res. 12, 3657–3660 (2006). &
- Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003). , , &
- Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10, 513–525 (2009).
- Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19–30 (2009). et al.
- Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment. Semin. Cancer Biol. 21, 83–88 (2011). , , , &
- Critical determinants of melanoma metastasis. J. Investig. Dermatol. Symp. Proc. 1, 203–208 (1996).
- The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation. J. Biol. Chem. 277, 8312–8320 (2002). et al.
- Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. J. Natl. Cancer Inst. 57, 1199–1202 (1976). &
- Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 69, 7529–7537 (2009). et al.
- The S100A8-serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 10, 1349–1355 (2008). et al.
- Regulators of endothelial and epithelial barrier integrity and function in acute lung injury. Biochem. Pharmacol. 77, 1763–1772 (2009). , , &
- Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009). &
- Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2, 180 (2011). et al.
- Characterization of plasma membrane shedding from murine melanoma cells. Int. J. Cancer 41, 629–635 (1988). , , &
- CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat. Rev. Cancer 11, 254–267 (2011).
- The HGF/c-Met axis synergizes with G-CSF in the mobilization of hematopoietic stem/progenitor cells. Stem Cells Dev. 19, 1143–1151 (2010). , , , &
- Enhanced c-Met activity promotes G-CSF–induced mobilization of hematopoietic progenitor cells via ROS signaling. Blood 117, 419–428 (2011). et al.
- Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner. Cancer Lett. 283, 168–175 (2009). , , , &
- High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS ONE 4, e5219 (2009). et al.
- Examining the metastatic niche: targeting the microenvironment. Semin. Oncol. 37 (suppl. 2), S2–S14 (2010).
- 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). 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). et al.
- Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 17, 867–874 (2011). et al.
- Priming the 'soil' for breast cancer metastasis: the pre-metastatic niche. Breast Dis. 26, 65–74 (2006). , , &
- Neoplastic Diseases: A Treatise on Tumours, 3rd edn. (W.B. Saunders Co., Philadelphia, 1928).
- The distribution of secondary growths in cancer of the breast. Lancet 133, 571–573 (1889).
- Proinvasion metastasis drivers in early-stage melanoma are oncogenes. Cancer Cell 20, 92–103 (2011). et al.
- c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 225, 1–26 (2005). , &
- An integrated approach to uncover drivers of cancer. Cell 143, 1005–1017 (2010). et al.
- 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). , , , &
- Effect of the secretory small GTPase Rab27B on breast cancer growth, invasion, and metastasis. J. Natl. Cancer Inst. 102, 866–880 (2010). et al.
- Supplementary Text and Figures (1.94 MB)
Supplementary Figures 1–7 and Supplementary Tables 1–5