Abstract 6443: Glia committed progenitor cells orchestrate medulloblastoma relapse

Abstract Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. Genomic-based classification has stratified MB into four molecular subgroups: Wingless/Int-1 (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4. This classification has significantly improved our understanding of MB and facilitated the development of better treatments. However, despite these advancements, approximately 30% of children with MB experience relapse. Recurrent MB is often metastatic, and nearly all children with relapse succumb to the disease within one year, underscoring the urgent need for therapies to prevent recurrence. Tumor relapse in MB is thought to be driven by progenitor cells resembling stages of the neuronal stem cell lineage. These quiescent cells are less susceptible to therapies targeting dividing cells and are therefore unlikely to be driven by mechanisms distinct from the bulk tumor. In our recent work, we described a population of Smoothened (SMO) inhibitor-resistant SRY-box 2 (SOX2)-labeled progenitor cells that facilitate MB recurrence. Single-cell transcriptomic analyses identified these SOX2+ cells as astrocyte progenitor cells (APCs) and revealed their dependence on GLI activity for propagation. In line with this dependency, inhibiting GLI-driven transcription not only reduced tumor size but also depleted APCs, leading to tumors less likely to relapse. However, some treated tumors retained the ability to engraft in vivo, suggesting that additional cells or mechanisms contribute to recurrence. Further studies identified therapy-resistant oligodendrocyte progenitor cells (OPCs) as another population driving MB relapse. OPCs, marked by OLIG2 expression, were enriched following treatment with GLI/SMO inhibitors and standard chemotherapy. Transcriptomic analyses revealed that Nuclear factor-κB (NF-kB) signaling, activated by tumor necrosis factor-alpha (TNF-α) release from microglia, promotes OPC enrichment. Therefore, inhibiting NF-kB signaling in ex vivo and in vivo models prevented therapy-induced OPC enrichment and significantly reduced tumor self-renewal capacity. In conclusion, therapeutic debulking of MB leads to the enrichment of glia-committed progenitor cells (APCs and OPCs), which drive recurrence. Combining therapies that target MB growth with agents that deplete or prevent progenitor cell enrichment may be necessary to prevent relapse. Citation Format: Kendell Peterson, April Salvador, Pritika Shahani, Maria Turos-Cabal, Valentin Kliebe, Jezabel Rodriguez-Blanco. Glia committed progenitor cells orchestrate medulloblastoma relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6443.