TMOD-29. Animal Free Modeling of Diffuse Intrinsic Pontine Glioma using a Human Neural Organoid

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an extremely aggressive and lethal childhood brain cancer that grows within the midbrain and along the brainstem. A major challenge limiting the preclinical study of DMG is the lack of reliable preclinical models. In vivo mouse models are expensive and technically challenging and in vitro cell culture models lack the essential components of tumor microenvironment (TME) needed to recapitulate the complex biology of these tumors. Human neural organoids with a multi-cellular make-up can serve as a cost effective and reliable model system to capture DMG biology in vitro. Using 3 separate PDX cell lines of DMG, we spatially profiled a novel human iPSC derived neural organoid containing functional astrocytes and microglia with the Nanostring GEOMX system. We found that all three cell lines interact with and quickly overtake the human neural organoids, demonstrating favorable growth conditions in a complex co-culture. Across spatially resolved ROI’s tumor cells can be seen individually interacting with microglia and astrocytes and transcriptomic profiling of these mixed cell ROI’s shows differences in the genetic signatures of both the normal cells (microglia/astrocytes) and the tumor cells. When compared to biopsies obtained directly from DIPG patients, DIPG cells within neural organoids look remarkably similar at both transcriptomic and proteomic levels. This study provides a proof of concept for neural organoid modeling for DIPG and underscores the translational relevance of this model system for high throughput genetic testing and drug discovery.