TMOD-16. HYPOXIA RESHAPES THE GLIOBLASTOMA MICROENVIRONMENT INVOKING NECROSIS AND TRIGGERING DISEASE PROGRESSION

Abstract

Abstract Emerging necrosis within solid tumors corresponds with malignant progression. Current tumor model systems fail to adequately mimic the magnitude of post-necrotic restructuring within the microenvironment and remain overly reliant on post-mortem and descriptive analyses, obligating researchers to extrapolate causal relationships between necrosis and progression phenomena that emerge during tumor evolution. In glioblastoma (GBM; WHO grade 4), the most malignant primary brain tumor, vascular pathology and central necrosis precede rapid, radial expansion. Despite extensive genetic characterization in GBM, mechanisms enabling selective fitness within a hypoxic/anoxic setting remain poorly understood. Persistent nutrient deprivation culminates in necrosis, dramatically altering the tumor microenvironment (TME). We established mouse models that more aptly capture events found in human gliomas, exposing the dynamic temporal and spatial changes that facilitate expansive progression while including unique microenvironmental stressors typically absent from GBM animal models, specifically central necrosis. This model combines hypoxia-induced focal necrosis within GBM with real time intravital microscopy to capture TME restructuring and elucidate its impact on glioma progression. Our studies use genetically characterized patient-derived orthotopic GBM xenografts, alongside an immunocompetent RCAS/tv-a model, to determine how these processes impact disease progression and outcomes across multiple GBM molecular subtypes. Simultaneously, we employ in vitro models to scrutinize how hypoxia-related crosstalk between GBM, microglia and circulating monocytes alter tumor-associated macrophage (TAMs) recruitment and reprogramming. Our preliminary data suggests microenvironmental cues significantly alter microglia behavior and have demonstrated increased 3D invasion under hypoxic conditions as compared to normoxia. Monocyte invasion varies based on signals emanating from specific GBM subtypes, yet the signaling events that elicit differential responses remains unknown. However, exposure to any GBM conditioned media uniformly upregulates immunosuppressive TAM programming. Our ongoing investigations seek to uncover the mechanisms driving post-necrotic GBM evolution and reactive neuroinflammation