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

By H. Peinado, M. Alečković, S. Lavotshkin, Irina R Matei, B. Costa-Silva, G. Moreno-Bueno, M. Hergueta-Redondo, Caitlin Williams, G. García‐Santos, Ayuko Nitadori-Hoshino and 14 more. Nature Medicine, 2012

3,522 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/24cea7c2d063e62dd6589dadadc77fa284948b30

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Citations in the corpus

Tumor-associated macrophages: from mechanisms to therapy (2014, background): “Myeloid cells also promote mesenchymal-to-epithelial transition (MET) and tumor growth by inhibiting TGF-b signaling in these epithelial metastatic cells (Gao et al., 2012).”
The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “This oncoprotein is overexpressed in bone marrow progenitor cells by exosomes from melanoma cells which in turn promotes tumor progression (164).”
Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development (2013, background): “Interestingly, recent studies have shown that the tumorigenic and prometastatic functions of exosomes could be efficiently counteracted by inhibition of the small GTPase Rab27a (44, 45), which has been shown to be involved in exosome formation (46).”
Biological properties of extracellular vesicles and their physiological functions (2015, background): “The protein and RNA content of plasma-derived EVs, aswell as the number of EVs present, has been shown to be altered by several pathological states, suggesting that blood can also harbor an EV population derived, for example, from tumours (95,324).”
Exosomes in cancer: small particle, big player (2015, background): “Exosomes from highly metastatic melanoma enhance the metastatic ability of primary tumors by converting bone marrow progenitor cells to a pro-vasculogenic and pre-metastatic phenotype via the MET receptor [39].”