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

Abstract

Tumor-derived exosomes are emerging mediators of tumorigenesis with tissue-specific addresses and messages. We explored the function of melanoma-derived exosomes in the formation of primary tumor and metastases in mouse and human subjects. Exosomes from highly metastatic melanoma increased the metastatic behavior of primary tumors by permanently “educating” bone marrow (BM) progenitors via the MET receptor. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitors towards a c-Kit+Tie2+Met+ pro-vasculogenic phenotype. Reducing Met expression in exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was elevated in circulating CD45−C-KITlow/+TIE2+ BM progenitors from metastatic melanoma subjects. RAB1a, RAB5b, RAB7, and RAB27a were highly expressed in melanoma cells and Rab27a RNA interference decreased exosome production, preventing BM education, tumor growth and metastasis. Finally, 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.

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

“…Another kind of nanoparticle is the liposome, which has the longest circulation time, when with a particle size between 80 and 150 nm, instead of being quickly eliminated by the liver or spleen 150. If EVs behave in the same way, the superior effect of Exos (or small EVs) for therapeutic use could be due to the peak of Exos particle size distribution being in the 80–150 nm range 28, 151. However, further study of EV subtypes is still needed.…”

“…The composition of cancer‐derived EVs (C‐EVs) is markedly changed compared to EVs from healthy cells, and C‐EVs can therefore be used as diagnostic biomarkers of cancers 25, 26. As key players in the field of liquid biopsies, C‐EVs are potential biological markers that can detect the existence of tumor cells, even in very early stages, and can be used to monitor the progression of malignant tumors 27, 28. In addition to studies showing that EVs are characterized by specific membrane proteins,29 the nucleic acid contents of C‐EVs in the plasma/serum from malignant tumor patients are also markedly different than those from healthy controls, indicating that the specific nucleic acid content in C‐EVs should be the focus of greater attention in the search for new tumor biomarkers 30, 31.…”

Emerging findings into molecular mechanism of brain metastasis

“…Nevertheless, a lot of brain‐derived factors are developed in recent studies, including secreted proteins and microRNA‐containing exosomes which alter the brain microenvironment to facilitate the survival and growth of BM 12, 13. Extracellular vesicles (EVs) including exosomes, mediate cell to cell communication with the delivery of their contents and then adjust multiple factors of malignancy in cancer cells 14, 15. The EVs which released from brain metastatic cancer cells could induce tight junction proteins like N‐cadherin or actin filaments located by mistake, and that may lead to the destruction of the cell to cell connection.…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Whether fibroblasts are a stromal source of these pro-inflammatory factors remains to be determined. Recently, signalling by tumour cell-derived exosomes was found to contribute to the crosstalk between the primary tumour and bone marrow-derived cells, leading to the homing of both cell types to sites of metastasis [116]. Tumour-secreted exosome-mediated signalling may also be relevant for activation of fibroblasts at metastatic sites.…”