(100e) Glioblastoma Organoids Model Extracellular Matrix Heterogeneity

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with a prognosis of 12-15 months. The aggressiveness of GBM is highly attributed to its heterogeneity of the tumor microenvironment (TME). Current in vitro models of GBM offer limited translation to in vivo tumors because of the heterogeneous TME, leading to limited progress in drug development and treatment. Organoids are millimeter-scale, 3D in vitro modeling systems that recapitulate stem cell differentiation into highly organized, heterogeneous in vivo organ-like systems. Here, we used defined engineering parameters on single GSCs to grow and develop into GBM organoids (GBOs) with a diameter up to 4.0 mm in 3 months or less, without the use of media-induced differentiation or extracellular matrix (ECM) mimicking scaffolds. We found our GBOs self-induced differentiation and organized cells into some key components of the GBM TME (i.e. hypoxic niche, angiogenesis, and necrotic core). Interestingly, the GBOs also self-secreted and organized its own key ECM components (i.e. collagen IV, elastin, laminin, and hyaluronic acid). Through our studies, we aim to understand what induces GSC differentiation and ECM redesign to form the heterogeneous TME and how this dynamic TME leads to varying drug response.