The metastatic microenvironment: Melanoma–microglia cross-talk promotes the malignant phenotype of melanoma cells

Sivan Izraely, Shlomit Ben-Menachem, Orit Sagi-Assif, Alona Telerman, Inna Zubrilov, Ofir Ashkenazi, Tsipi Meshel, Shelly Maman, Javier I.J. Orozco, Matthew P. Salomon, Diego M. Marzese, Metsada Pasmanik-Chor, Eli Pikarski, Marcelo Ehrlich, Dave S.B. Hoon, Isaac P. Witz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia-mediated 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-metastasizing 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-2 (MMP-2) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP-2 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.

Original languageEnglish
Pages (from-to)802-817
Number of pages16
JournalInternational Journal of Cancer
Issue number4
StatePublished - 15 Feb 2019


  • brain metastasis
  • melanoma
  • microglia


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