P02.21.B IMMATURE NEURONAL NICHES AND ECM REMODELING CONTRIBUTE TO EPILEPTOGENICITY IN GANGLIOGLIOMAS: INSIGHTS FROM SPATIAL TRANSCRIPTOMICS

Abstract BACKGROUND Gangliogliomas (GGs) are rare glio-neuronal tumors frequently associated with pharmacoresistant focal epilepsy. Although patients often achieve favorable seizure outcomes following surgery, the cellular and molecular basis of epileptogenesis in GGs remains poorly understood. In this study, we focus on the role of extracellular matrix (ECM) remodeling and immature neuronal components in shaping the tumor microenvironment and driving epileptogenicity. MATERIAL AND METHODS We analyzed spatial transcriptomic profiles of eight GG samples (BRAF wild-type, n = 3; BRAF-mutant, n = 5) using the 10X Visium platform. Data were processed with SPATA2. Cell type deconvolution (cell2location) and Weighted Gene Correlation Network Analysis (WGCNA) were applied to characterize transcriptional programs within the tumor microenvironment. RESULTS WGCNA identified eight transcriptional modules reflecting distinct cellular programs. These included signatures of astrogliosis and oligodendroglial reactivity with active myelination (GFAP, S100A1, MBP, PLP1), as well as neuron-rich clusters enriched for synaptic signaling (SNAP25, SYP; p < 0.001) and plasticity-associated genes (ENC1, CHGA, CHGB; p < 0.001). Immature neuronal populations showed enrichment for progenitor-like genes (FABP7, HOPX), indicative of impaired neuronal maturation. Additional clusters reflected reactive gliosis (THY1, PDGFRA, SERPINA3; p < 0.001) and immune infiltration involving microglia and macrophages (CD63, FGF12, S100A10; p < 0.001), suggesting immune-tumor interactions. ECM-related transcriptional programs were upregulated in regions with histological evidence of matrix remodeling and pial boundary disruption, implying increased infiltrative potential—features previously linked to higher seizure risk and recurrence. CONCLUSION GGs are composed of both glial and neuronal elements, including a population of progenitor-like neuronal cells and infiltrating immune components. Our findings highlight inflammatory ECM remodeling as a central feature that shapes the tumor microenvironment and might interact with immature and dysfunctional neuronal populations to promote epileptogenicity.