CNSC-87. NF-ΚB ENABLES THE RESISTANCE OF OLIGODENDROCYTE PRECURSOR-LIKE MB CELLS TO THERAPIES

Abstract Malignant brain tumors are the leading cause of cancer-related death in children, with medulloblastoma (MB) being the most common. Despite aggressive treatment, relapse occurs in ~30% of cases. Recurrent MB is typically metastatic, and survival after relapse rarely exceeds one year. Recent studies have identified oligodendrocyte precursor-like (OPC-like) MB cells as key drivers of relapse, but the mechanisms by which these cells evade therapy remain unclear. METHODS We used a three-pronged approach—integrating single-cell and bulk transcriptomic analyses with prior literature—to identify candidate OPC drivers. The role of a lead candidate in promoting OPC resistance was tested in MB cultures and allograft models. RESULTS Our findings indicate that cytotoxic therapies activate microglia, which release cytokines that stimulate Nuclear factor-ΚB (NF-ΚB) signaling in tumor cells. This activation upregulates OPC-associated genes such as Sox10 and Olig2. Importantly, inhibition of NF-ΚB signaling in ex vivo and in vivo models prevented therapy-induced OPC enrichment and reduced tumor self-renewal. CONCLUSION Given the established role of OPC-like cells in MB relapse, combining cytotoxic therapies with NF-ΚB pathway inhibitors may be essential to prevent recurrence and improve outcomes for children with this devastating disease.