EPCO-34. GBM GROWTH MODE IS GOVERNED BY EPIGENETIC REPROGRAMMING OF TUMOR-ASSOCIATED MICROGLIA

Abstract The invasive nature of glioblastoma (GBM), the most common malignant primary brain tumor, makes it complete resection impossible. Microglia, the brain’s resident immune cells, typically contribute to neural homeostasis, but their role in regulating GBM invasion remains poorly understood. Using a highly infiltrative murine GBM model in immunocompetent mice (KR158 intracranial transplants), we retraced the early invasion steps and interactions of GBM cells with tumor-associated microglia (TAMs). We demonstrate that TAMs are activated within a wide tumor field preceding GBM invasion and subsequently form glial nets that encircle invading tumor cells. Crucially, the programming status of TAMs dictated whether GBM tumors expanded via infiltrative or bulk growth modes. We identified the histone H3K27me3 demethylase Kdm6b as being induced in TAMs within the pre-invasion field. Pharmacological inhibition of Kdm6b with GSK-J4 disrupted TAM programming and shifted GBM growth towards a bulk expansion mode. Intriguingly, GBM dissemination was significantly more extensive in juvenile host brains, correlating with elevated Kdm6b expression, pointing to a role of age in microglial programming. Collectively, our data reveal that microglial programming via epigenetic modifications determines GBM invasion modes, offering insights for new therapeutic strategies to halt GBM progression.