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Heterogeneity in the metastatic microenvironment: JunB-expressing microglia cells as potential drivers of melanoma brain metastasis progression

ABSTRACT: Reciprocal signaling between melanoma brain metastatic (MBM) cells and microglia reprograms the phenotype of both interaction partners, including upregulation of the transcription factor JunB in microglia. Here, we aimed to elucidate the impact of microglial JunB upregulation on MBM progression. For molecular profiling, we employed RNAseq and RPPA. To test microglial JunB functions we generated microglia variants stably overexpressing JunB (JunBhi) or with downregulated levels of JunB (JunBlo). Melanoma-derived factors, namely Leukemia Inhibitory Factor (LIF), controlled JunB upregulation through JAK/STAT3 signaling. The expression levels of JunB in melanoma-associated microglia were heterogeneous. Flow cytometry analysis revealed the existence of basal-level JunB expressing microglia alongside JunB-highly expressing microglia. Proteomic profiling revealed a differential protein expression in JunBhi and JunBlo cells, including in the expression of microglia activation markers Iba-1 and CD150, and in immunosuppressive molecules SOCS3 and PD-L1. Functionally, JunBhi microglia displayed decreased migratory capacity and phagocytic activity. JunBlo microglia reduced melanoma proliferation and migration, while JunBhi microglia supported the ability of melanoma to proliferate in 3-dimensional co-cultures, that was abrogated by targeting LIFRβ in melanoma-microglia spheroids. Altogether, these data highlight a melanoma-mediated heterogeneous effect on microglial JunB expression, which turns these cells into functionally heterogeneous microglia. Targeting JunB highly-expressing microglia may potentially be utilized for MBM theranostics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240905 | GEO | 2025/10/15

REPOSITORIES: GEO

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Heterogeneity in the metastatic microenvironment: JunB-expressing microglia cells as potential drivers of melanoma brain metastasis progression

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