TMIC-48. HYPOXIC AND PERI-NECROTIC ZONES IN GLIOBLASTOMA CAUSE HIPPO-OFF SIGNALING, POTENTIALLY SUPPORTING GLIOMA STEM CELLS

Abstract Glioblastoma (GBM) is the most common and malignant primary brain tumor with pre-necrotic post-necrotic growth phases. The development of necrosis associated extensive micro-environmental (TME) rearrangement rapid biologic advancement. Compared to GBMs, GBMs are heterogenous contain multi-focal regions surrounded by pseudopalisading cells characterized severe hypoxia. Hypoxic, peri-necrotic zones highly enriched for glioma stem (GSCs) macrophages (TAMs), latter accounting 30-40% total cellularity. Using Ivy-GAP data, we performed gene set enrichment analysis (GSEA) stem-cell markers, comparing non-necrotic regions. We also used TCGA/CGGA data identify correlations between hypoxia markers classic (SOX2, SOX9, nestin, STAT3, prominin). None these showed in zone or association markers. However, uncovered strong associations Hippo-off signaling regions, signifying activation YAP/TAZ transcriptional activation. therefore hypothesized that (YAP/TAZ activation) hypoxic promotes GSC self-renewing division. To support this, GSEA Hippo pathway readout genes found regulated CYR61, BIRC2, SERPINE1 AREG. patient-derived GBM neurosphere cultures, exposed 1% p-YAP1 p-TAZ protein levels were downregulated compared normoxia (21%) at 24 hrs, correlating Hippo-on. targets upregulated, indicating transcription. Ivy-GAP, TCGA CGGA peri-necrotic/hypoxic two cytokines, IL-1β IL-6, known trigger cytokine multiplex analysis, observed an upregulation both IL-6 secretion from monocytes microglia, raising possibility cytokines directly stimulate promote division niche.