CNSC-24. NEURONAL ACTIVITY PROMOTES GLIOMA PROGRESSION THROUGH INDUCING RNA M6A DEMETHYLATION AND PRONEURAL-TO-MESENCHYMAL TRANSITION IN GLIOMA STEM CELLS

Abstract

Abstract High-grade gliomas are lethal brain cancers whose progression is highly driven by neuronal activity. The glioma stem cell (GSC) subpopulation has been identified in glioblastoma and plays a significant role in the resistance of glioma to conventional therapies as well as cancer recurrence. Activity-regulated release of growth factors and electrical synaptic integration promotes glioma growth; however, it is unclear whether neuronal activity plays a role in the mRNA N6-methyladenosine (m6A) level changes in patient glioma tissue. By using chemogenetics techniques, we enhanced and inhibited neuronal activity in vitro and in vivo, and studied how neuronal activity regulates GSC behaviors. Here, we identified that neuronal activity promotes glioma progression and radioresistance through neuronal exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. We revealed that neuronal activity upregulates critical microRNA expression in NDEs (neuro-derived exosomes) and subsequently induces PMT by activating the STAT3 pathway. Chemogenetically activating cortical neurons increases the growth of GSC xenografts in situ. Conversely, reducing neuronal activity inhibited the GSC xenograft growth. Anti-seizure medication treatment suppresses GSC PMT and sensitizes GSCs to radiotherapy in vitro and in vivo. Together, these findings indicate that exosomes of active neurons can promote glioma progression and radioresistance by inducing GSC PMT via neuro-derived extracellular vesicles