P02.22.A HYPOXIA-DRIVEN EGFR SIGNALING PROMOTES A QUIESCENT-ACTIVATION AXIS IN IDH-MUTANT LOW-GRADE GLIOMAS

Abstract BACKGROUND Hypoxia is a recognized driver of transcriptional heterogeneity in high-grade glioblastoma (GBM), yet its functional significance in low-grade gliomas (LGGs) remains poorly understood. We hypothesized that hypoxia orchestrates a reversible quiescence-activation axis in LGGs via EGFR-dependent transcriptional reprogramming, thereby influencing tumor progression. MATERIAL AND METHODS We conducted integrative analyses of single-cell RNA sequencing (n=7 patients) and spatial transcriptomics (n=8 samples) across molecularly defined IDH-mutant LGGs to delineate hypoxia-associated transcriptional states. EGFR mutation, and clinical correlations with overall survival, were assessed in The Cancer Genome Atlas (TCGA) bulk RNA-seq cohorts. To functionally validate microenvironmental contributions, we established innovative co-culture models of LGG cells with hypoxia-conditioned primary microglia and astrocytes. RESULTS We identified a hypoxia-associated, LGG-specific ribosomal-enriched (RE) transcriptional program characterizing a non-cycling subpopulation enriched in quiescence and activation stages. Quiescent RE cells exhibited glioma stem cell (GSC)-like features, with EGFR signaling dependency for transition to an activated phenotype. Spatial transcriptomics revealed distinct co-localization of hypoxia, RE program expression, and quiescent states, whereas EGFR-activated cells formed discrete micro-niches. Hypoxia-conditioned microglia significantly enhanced RE program activation and EGFR signaling, establishing a functional microenvironmental driver of phenotypic plasticity. CONCLUSION Our findings delineate a novel hypoxia-EGFR signaling axis sustaining a quiescent yet activation-capable subpopulation in IDH-mutant LGGs. These insights nominate hypoxia-modulated EGFR pathways as potential therapeutic targets to disrupt tumor cell plasticity. Future studies will interrogate vulnerabilities of RE-programmed LGG cells under hypoxic conditions to inform next-generation therapeutic development.