The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway

Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucidated a pro-metastatic molecular mechanism that drives a vicious melanoma-brain-metastasis cycle. We employed RNA-Sequencing, HTG miRNA whole transcriptome assay, and reverse phase protein arrays (RPPA) to analyze the impact of melanoma-microglia interactions on sustainability and progression of four different human brain-metastasizing melanoma cell lines. Microglia cells exposed to melanoma-derived IL-6 exhibited upregulated levels of STAT3 phosphorylation and SOCS3 expression, which, in turn, promoted melanoma cell viability and metastatic potential. IL-6/STAT3 pathway inhibitors diminished the pro-metastatic functions of microglia and reduced melanoma progression. SOCS3 overexpression in microglia cells evoked microglial support in melanoma brain metastasis by increasing melanoma cell migration and proliferation. Different melanomas exhibited heterogeneity in their microglia-activating capacity as well as in their response to microglia-derived signals. In spite of this reality and based on the results of the present study, we concluded that the activation of the IL-6/STAT3/SOCS3 pathway in microglia is a major mechanism by which reciprocal melanoma-microglia signaling engineers the interacting microglia to reinforce the progression of melanoma brain metastasis. This mechanism may operate differently in different melanomas.

Automated summary

Previous studies have shown that the interaction between brain-metastasizing melanoma cells and microglia plays a crucial role in promoting metastasis. In this study, we conducted a comprehensive investigation of melanoma-microglia interactions and discovered a pro-metastatic molecular mechanism that drives the melanoma-brain metastasis cycle. By analyzing different human brain-metastasizing melanoma cell lines, we found that exposure of microglia cells to melanoma-derived IL-6 resulted in increased STAT3 phosphorylation and SOCS3 expression, leading to enhanced melanoma cell viability and metastatic potential. Inhibitors targeting the IL-6/STAT3 pathway diminished the pro-metastatic functions of microglia and reduced melanoma progression. Furthermore, overexpression of SOCS3 in microglia cells increased melanoma cell migration and proliferation, providing support for melanoma brain metastasis. However, different melanomas exhibited heterogeneity in their ability to activate microglia and respond to microglia-derived signals. Overall, the activation of the IL-6/STAT3/SOCS3 pathway in microglia appears to be a major mechanism by which melanoma-microglia signaling contributes to the progression of melanoma brain metastasis.