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Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable \u201cpremetastatic niche.\u201d Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma\u2010derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound\u2010healing functions, suggesting that tumor cell\u2010secreted EVs activate distinct CAF characteristics and tumor\u2010promoting functions. Moreover, melanoma\u2010secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV\u2010mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma\u2010derived EVs reprogram tumor\u2010promoting functions in stromal cells in a distinct manner, implicating a central role for tumor\u2010derived EV signaling in promoting the formation of an inflammatory metastatic niche.<\/jats:p>","DOI":"10.1002\/ijc.32521","type":"journal-article","created":{"date-parts":[[2019,6,19]],"date-time":"2019-06-19T12:23:45Z","timestamp":1560947025000},"page":"2521-2534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Melanoma\u2010derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment"],"prefix":"10.1002","volume":"145","author":[{"given":"Tzlil","family":"Gener Lahav","sequence":"first","affiliation":[{"name":"Department of Pathology, Sackler School of Medicine Tel Aviv University  Tel Aviv 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