Regulation of Asymmetric Cellular Division in Glioma Stem Cells

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DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common and most malignant primary brain tumor. Recent studies suggest that a small subset of neoplastic cells, referred to as Glioma Stem Cells (GSCs), may govern the biologic behavior of GBM. GSCs have properties of self-renewal, pluripotency and high tumorigenicity. They have thus far been identified by the expression of specific markers, such as CD133, Sox2 and nestin, yet molecular mechanisms responsible for stem-like behavior have not been clearly defined, nor have regulators of the stem/non-stem equilibrium. This proposal aims to define molecular mechanisms that confer stem-like qualities to GSCs and enriches their presence in GBMs. Pathways that direct asymmetric cellular division and stem-like behavior in the Drosophila melanogaster nervous system have been well described and may provide clues to stem cell properties and the stem/non-stem balance in malignant gliomas. The Drosophila brain tumor (brat) gene product regulates asymmetric cell division through its segregation into the daughter cell destined for differentiation, where it functions to translationally repress Myc. In brat mutants, asymmetric division and neural differentiation do not occur, leading to a massively enlarged larval brain containing highly proliferative undifferentiated neuroblastic cells with neoplastic properties. The human homolog of Drosophila brat, Trim3, shows allelic loss in over 25% of GBMs and reduced expression in nearly all. In the current proposal, we hypothesize that reduced expression of Trim3, or its interacting proteins, is critical in defining stem-like properties in human GSCs by favoring a loss of asymmetric cell division and enriching the stem cell compartment. We propose to investigate Trim3 in human gliomas in order to determine if its expression is downregulated in human GBMs; if Trim3 regulates c-Myc protein expression and activity in vitro and in vivo; if Trim3 regulates stem like properties of human in GBM neurosphere cultures and GBM resection specimens; if genetic and hypoxic mechanisms regulate Trim3 during tumor progression; and if Trim3 regulates the in vivo growth properties of GBM in animal models. PUBLIC HEALTH RELEVANCE: 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) have recently been identified as a biologically potent subset of GBM cells, yet mechanisms underlying their specialized properties are not understood. The current proposal attempts to define mechanisms that underlie GSC properties in GBM, which could lead to better therapies.