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We investigate mechanisms of progression to glioblastoma (GBM), the highest grade astrocytoma, including genetics, hypoxia, glioma stem cells and angiogenesis. In all instances, progression is characterized by the development of tumor necrosis, severe hypoxia and microvascular hyperplasia, a type of angiogenesis. Based on prior work, we have proposed that vaso-occlusion and intravascular thrombosis within a high-grade glioma results in hypoxia, necrosis and hypoxia-induced microvascular hyperplasia in the tumor’s periphery, leading to neoplastic expansion outward. We have initiated a xenograft mouse model in which a fluorescently labeled human glioma is implanted under a skull window and these events can be viewed directly. We induce thrombosis in the tumor by photo-activating Rose Bengal within the blood stream, which causes focal thrombosis and can track subsequent events, including the influx and activation of macrophages, the enrichment of stem cells and the development of angiogenesis. We are also using samples from patients with GBM to determine if regions from distinct tumor micro-environments that arise from these events have differing transcriptional profiles, signaling networks, and therapeutic targets.

We also study mechanisms that confer specialized biologic properties to glioma stem cells (GSC) in GBM, including their ability to divide asymmetrically and their enrichment in hypoxic micro-environments. The Drosophila brain tumor (brat) gene normally regulates asymmetric cellular division and neural progenitor differentiation in the brains of flies and, when mutated, leads to a massive brain containing only neuroblastic cells with tumor-like properties. We study the human homolog of Drosophila brat, Trim3, for its role in regulating asymmetric cell division and stem-like properties in GSC and have developed screening methods to uncover which pathways or specific protein kinases might be the most appropriate targets to reverse the stem cell phenotype in Drosophila and mammalian models. We are currently focused on the unconventional cyclin-dependent kinase CDK5 and its binding partner p35, since we found that their suppression diminishes the stem cell phenotype.

We have initiated an In Silico Center for Brain Tumor Research to investigate the molecular correlates of pathologic, radiologic and clinical features of gliomas using pre-existing databases, especially the cancer genome atlas project (TCGA). Using molecular datasets and image analysis algorithms, we study whether tumor cell morphology or elements of the tumor micro-environment, such as tumor necrosis, angiogenesis, or inflammatory infiltrates, correlate with molecular profiles or clinical behavior in TCGA glioma’s and validate our findings with patient cohorts.