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Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia\u2010mediated neuroinflammation in facilitating melanoma brain metastasis are lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain\u2010metastasizing melanoma cells and microglia cells after the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling, and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase\u20102 (MMP\u20102) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP\u20102 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bidirectional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation.<\/jats:p>","DOI":"10.1002\/ijc.31745","type":"journal-article","created":{"date-parts":[[2018,7,11]],"date-time":"2018-07-11T04:48:51Z","timestamp":1531284531000},"page":"802-817","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["The metastatic microenvironment: Melanoma\u2013microglia cross\u2010talk promotes the malignant phenotype of melanoma cells"],"prefix":"10.1002","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1000-5708","authenticated-orcid":false,"given":"Sivan","family":"Izraely","sequence":"first","affiliation":[{"name":"Department of Cell Research and Immunology, George S. 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