2026 Proffered Presentations
S049: RNA SEQUENCING REVEALS RADIATION-ASSOCIATED REPROGRAMMING OF HYPOXIA PATHWAYS IN HIGH-GRADE MENINGIOMAS
Ishav Y Shukla, BS; Jeffrey I Traylor, MD; Hunter Flores, BS; Aaron Plitt, MD; Matthew Z Sun, MD; UT Southwestern Medical Center
Introduction: Radiation therapy (RT) is central to the management of high-grade meningiomas, especially for recurrent or residual disease. Beyond cytotoxicity, RT reshapes the tumor microenvironment, altering vascular integrity, oxygen availability, and stress responses, thereby amplifying hypoxia and reprogramming genes essential for metabolism, angiogenesis, and survival. Defining how RT modulates hypoxia-associated transcriptional programs in meningiomas remains an unmet need. The objective of this study was to characterize hypoxia-related transcriptomic alterations in grade 3 meningiomas following RT compared with radiation-naïve tumors.
Methods: RNA-seq data were obtained from three separate studies available in the NCBI Gene Expression Omnibus (GEO) database: cadaveric dura (n = 43), radiation-naïve grade 3 meningiomas (n = 7), and grade 3 meningiomas post-RT (n = 8). Differential expression was assessed using DESeq2, with log fold change (LFC) and false discovery rate (FDR, Benjamini–Hochberg adjusted p) reported. Genes of interest were categorized by hypoxia-related biological functions, including metabolic adaptation, angiogenesis, stress and survival pathways, and microenvironmental remodeling.
Results: Differential expression analysis of post-radiated versus radiation-naïve grade 3 meningiomas revealed significant remodeling of hypoxia-associated programs across multiple biological pathways. Angiogenic signaling was prominently induced, with VEGFA (LFC +2.14, p < 0.001) and ANGPTL4 (LFC +2.47, p = 0.002) both significantly upregulated. Oxygen-sensing and HIF regulation showed divergent responses, with HIF1A (LFC +1.19, p < 0.001) and EGLN1/PHD2 (LFC +2.00, p < 0.001) increased, while EGLN2/PHD1 was decreased (LFC −2.15, p < 0.001). Metabolic adaptation included significant reductions in ALDOA (LFC −1.83, p < 0.001) and PFKFB3 (LFC −1.02, p = 0.008), alongside non-significant increases in CA9 (LFC +1.42, p = 0.094), SLC2A1/GLUT1 (LFC +0.92, p = 0.287), and glycolytic enzymes such as ENO1 and HK2. Microenvironmental remodeling was characterized by induction of LOXL2 (LFC +2.59, p = 0.004), with trends toward upregulation of CXCR4 (LFC +1.14, p = 0.056). Other hypoxia-related transcripts trended without reaching significance, including NDRG1 (LFC −0.47, p = 0.364), DDIT4 (LFC −0.48, p = 0.240), PGK1 (LFC −0.19, p = 0.592), and SLC16A3/MCT4 (LFC +0.46, p = 0.469).
Conclusion: RNA sequencing of post-radiated grade 3 meningiomas revealed a distinct hypoxia-associated transcriptional program compared with radiation-naïve tumors. Angiogenesis was markedly increased through induction of VEGFA and ANGPTL4, while oxygen-sensing pathways were reshaped with upregulation of HIF1A and EGLN1 and suppression of EGLN2. Metabolic remodeling was defined by loss of ALDOA and PFKFB3 with trends toward increased CA9, GLUT1, and other glycolytic enzymes. Microenvironmental remodeling featured upregulation of LOXL2 and signals toward increased CXCR4. Additional transcripts, including NDRG1, DDIT4, PGK1, and SLC16A3, showed non-significant changes, suggesting broader but less consistent effects. Together, these data define a radiation-induced hypoxic transcriptomic shift across angiogenesis, HIF regulation, metabolism, and extracellular matrix remodeling. Induction of VEGFA/ANGPTL4 highlights angiogenesis as a target for anti-VEGF therapy after RT, suppression of PFKFB3 and ALDOA exposes metabolic vulnerabilities, and upregulation of LOXL2 implicates ECM-directed inhibitors. These findings provide a transcriptomic rationale for combining RT with anti-angiogenic, metabolic, and microenvironment-targeted therapies to improve outcomes in high-grade meningiomas.