TMOD-33. Single-cell atlas of pediatric brain tumors reveals targetable radial glia signatures in ependymoma

Abstract Pediatric brain tumors are a leading cause of cancer-related mortality in children, yet many subtypes remain poorly characterized at the cellular, developmental, and molecular levels. To address this gap, we performed a comprehensive single-cell RNA sequencing analysis across a diverse cohort of primary pediatric brain tumors, including ganglioglioma, DNET, pilocytic astrocytoma, pleomorphic xanthoastrocytoma (PXA), oligodendroglioma, diffuse astrocytoma, IDH mutant glioma, IDH wild-type glioblastoma, G34 diffuse hemispheric glioma, ependymoma, and atypical teratoid/rhabdoid tumor (ATRT). Tumor-derived transcriptomes were mapped to our previously published high-resolution reference atlas of the developing human brain to identify cell type signatures, specifically shared progenitor signatures. This revealed widespread enrichment of radial glia–like and early neurogenic populations in aggressive tumor types. PTPRZ1, a canonical radial glia marker, was among the most consistently expressed genes across tumor types. Its diffuse expression was confirmed by immunostaining in patient samples across multiple pediatric tumor pathologies. Notably, tumors with high PTPRZ1 expression, including G34 glioma, high-grade glioma, ATRT, and ependymoma, demonstrated robust enrichment for radial glia–like populations, suggesting a potential developmental dependency on this progenitor program. To functionally model these dependencies, we optimized a human tumor organoid co-culture platform to support the growth of freshly resected pediatric ependymoma tissue. Using single-cell RNA sequencing, we confirmed that this platform preserved the tumor’s cellular heterogeneity, including radial glia-like states. The ability to maintain and study these progenitor populations in vitro creates a powerful system for dissecting pediatric tumor progression and cellular states and allows for testing of therapeutic options. Our findings highlight conserved radial glial signatures as shared developmental programs across aggressive pediatric brain tumors and establish a patient-derived organoid model to interrogate their functional relevance in tumor biology.