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Asymmetric Cell Division Regulation of Glioma Stem Cells

In this project, we study mechanisms of asymmetric cell division in glioma stem cells (GSCs). In mammals, normal neural stem cells reside near the periphery of the ventricles in the proliferative zone and divide asymmetrically to give rise to two daughter cells; one daughter retains its role as a neural stem cell and the other differentiates to generate a wide variety of neural and glial cells that populate the brain. A glioma stem cell however loses its normal asymmetric division and divides more symmetrically giving rise to cells that proliferate and feed the tumor growth. The mechanisms of asymmetric division is well-known in the fruit-fly Drosophila melanogaster. However, little is known about mammalian asymmetric division. We explore the deregulation of the asymmetric division using Drosophila model of brain tumor and translate our findings in human patient-derived tumor cells and mouse xenograft model of glioblastoma. 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 ortholog 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 Drosophilaand 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.