TMOD-14. ESTABLISHING A CLINICALLY RELEVANT MOUSE MODEL TO STUDY NECROSIS AS A PRIMARY VARIABLE IN GLIOBLASTOMA

Abstract All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. We suggest that necrosis is much more than a passive phenomenon related to rapid growth but rather is a driving force causing tumor microenvironment (TME) restructuring and biologic progression. yet mechanisms remain poorly understood due to a lack of animal models to study necrosis as a primary variable. In GBM, the most malignant primary brain tumor, vascular pathology and central necrosis precede rapid, radial expansion. To reveal spatio-temporal changes directly following vascular damage in the brain, we developed methodology to induce clinically relevant thrombosis vaso-occlusion within GBMs in immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression in real-time. We found that following Rose Bengal photothrombosis, GBMs rapidly expanded radially, with glioma migration away from central necrosis and tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increased dramatically in the peri-necrotic zones. Through the single cell tracking analysis, we found that TAMs displaying increased displacement toward necrosis and greater overall migration distances. Collectively, this model introduces necrosis as the primary variable and captures glioma growth dynamics and TME restructuring in a manner that will facilitate the development of therapies that antagonize these mechanisms to improve outcomes.