Abstract
Pediatric high-grade gliomas (pHGG) are among the most common childhood brain tumors. Distinct patterns of genetic alterations and pathological features have been identified based on regional location, including limited disruption of the blood-brain barrier in diffuse intrinsic pontine gliomas (DIPG). To determine the underlying differences in pHGG regional tumor-vascular interactions, we have started to perform histological and molecular analyses of normal and tumor vasculature. By utilizing in utero electroporation to target defined CNS regions, we have generated pHGG mouse models that develop in supratentorial and brainstem regions, and faithfully recapitulate features of the human disease. Preliminary analysis shows that brainstem gliomas display limited vascular abnormalities, and little to no vascular leakage, suggesting maintenance of the BBB. Interestingly, supratentorial pHGG contain core regions that display traditional vascular abnormalities normally associated with glioblastoma, including increased vascular permeability and hemorrhaging. Ongoing studies are being performed to determine underlying molecular differences between normal and tumor associated endothelial cells purified from supratentorial and brainstem regions. Overall, we hope to advance our understanding of vascular heterogeneity within the brain, and define mechanisms utilized by gliomas to modulate BBB function. By determining cell autonomous and non-autonomous differences that drive tumor angiogenesis and BBB disruption, we hope to identify molecularly targeted therapies to enhance drug penetration and responsiveness of pHGGs.