TMIC-52. HISTONE H3K27ME3 LEVEL GOVERN TUMOR-ASSOCIATED MICROGLIA REPROGRAMMING IN RESPONSE TO GBM

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor and its invasive nature makes complete dissection difficult. However, how GBM invade in the brain is poorly understood. Although, microglia are the resident immune cells in the brain that can support GBM invasion, their roles are yet elusive. Here, we retraced early steps of GBM invasion and their interaction with tumor-associated microglia (TAM) in a highly infiltrative murine GBM model in immunocompetent background. We show that microglia are activated in a wide tumor field ahead of GBM invasion, followed by glial net formation, encircling invading tumors. Next, physical contacts with GBM cells initiate an astounding morphological, and functional transformation of microglia and marrow-derived macrophages to form collectively organized migration streams with intertwined GBM cells. Here we show that Kdm6b, a H3K27me3 demethylase, is induced in TAMs during this process. Intriguingly, GBM disseminated more widely in juvenile host brains, which was associated with highly induced Kdm6b expression. Moreover, we show that Kdm6b inhibition with small chemical inhibitor GSKJ-4, perturbs TAM reprogramming, and GBM invasion. Together, our data reveal that microglia reprogramming provide directional cues for GBM invasion through epigenetic mechanisms and this may give insights to halt GBM invasion.