Spatial glia-to-glia crosstalk in brain metastatic progression

Glial cells play a critical role in shaping the tumor microenvironment in brain metastases, facilitating disease progression through complex tumor-glial and distinct glia-to-glia signaling pathways. To investigate these interactions, we performed RNA sequencing of astrocytes, microglia, and oligodendrocytes at various stages of brain metastatic progression, combined with spatial transcriptomics and cell-cell crosstalk analysis using CCCExplorer. Our findings reveal that while glial cells not only converge on tumor-promoting pathways such as Ras and Gap junction signaling in tumor cells, but also engage in distinct autocrine and paracrine signaling critical for their own communication. Unique ligand-receptor pairs including OSM-OSMR, CCL4-CCR5, CXCL16-CXCR6, IL1A/B-IL1R, and TNF-TNFR were identified as drivers of glial crosstalk, which sustains the tumor-supportive niche. Therapeutic targeting of CCL4-CCR5-mediated glial signaling with maraviroc, an FDA-approved antiviral drug, reduced brain metastasis progression by 62% (p=0.004) without directly inducing cytotoxicity to tumor cells. These results highlight a paradigm-shifting strategy that focuses on glial communication within the tumor microenvironment, offering a novel and less toxic therapeutic approach for managing brain metastases by disrupting the supportive glial niche rather than tumor cells directly.