Glioblastoma (GBM) is the most common and most malignant primary brain tumor and has a dismal prognosis. Abundant evidence now indicates that a small subset of neoplastic cells, referred to as Glioma Stem Cells (GSCs), governs biologic behavior and resistance to therapy. GSCs inhabit specific biologic niches and have properties of self-renewal, pluripotency and high tumorigenicity. They can be identified by expression of markers, such as CD133, CD15 and nestin, yet molecular mechanisms responsible for their specific stem-like behavior in glioblastomas have not been fully defined. This proposal aims to define mechanisms underlying fundamental biological properties of GSCs, including: 1) their marked accumulation following the development of necrosis and tendency to localize to the hypoxic niche; and 2) a disrupted program of asymmetric cell division that favors self-renewing division over differentiation. We have developed novel in vitro and in vivo models and analytic techniques to study the differential behavior of stem and non-stem glioma cells within the tumor micro-environment, especially as it relates to their accumulation in regions of hypoxia. These include an in vivo orthotopic xenograft model in which stem cells are interrogated for patterns and mechanisms of accumulation following the induction of necrosis using a photo-activated dye. We also dissect pathways that direct asymmetric cellular division in Drosophila nervous system provide clues to understand the stem/non-stem dynamics in malignant gliomas. We have previously demonstrated that the human ortholog of Drosophila Brat, Trim3, is a tumor suppressor that regulates glioma stem cell dynamics and promotes stemness when lost. Here we propose to investigate novel regulatory mechanisms that arise during transition to the stem cell phenotype that can be antagonized therapeutically. Regulatory networks and potential therapeutic targets are further explored in xenografts and genetically engineered mouse models that recapitulates human gliomas to show efficacy.
Glioblastoma (GBM) is a highly malignant brain tumor that is generally fatal within 18 months. Despite advanced understanding of GBM genetics and biology, new therapies have not led to substantial improvement in survival, highlighting the need to uncover driving biological mechanisms. Glioma stem cells (GSCs) are a biologically potent subset of GBM cells with distinct biological properties that are critical to tumor growth, treatment resistance and recurrence, yet therapies directed at their specialized functions have not been fully explored. The current proposal attempts to identify mechanisms underlying behaviors that are specific to glioma stem cells, including their accumulation and localization in response to hypoxia and their disrupted program of asymmetric cell division, in order to develop therapeutic approaches to suppress this subpopulation more effectively.
