Role of Ascl1 in glioma

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DESCRIPTION (provided by applicant): Primary malignant gliomas are incurable brain tumors that affect thousands of people every year. Although alteration of oncogenes and tumor suppressors genes have been described to contribute to the pathogenesis of gliomas, very little is known about the biology of glioma development or the genetic mechanisms that are essential for tumor formation and progression. Ascl1, a basic-helix-loop-helix (bHLH) transcription factor, is aberrantly upregulated in a number of cancers, including lung cancers with neuroendocrine features and malignant astrocytoma. Mouse models of malignant astrocytoma recently indicated that neural progenitors may be the cells of origin for glioma. Given that Ascl1 is expressed in neural progenitors during development as well as in the adult brain, and was recently shown to directly regulate cell cycle regulators, it is hypothesized that Ascl1 plays an important role in gliomagenesis. Preliminary evidence for the proposed project demonstrates that Ascl1 is highly expressed in a subset of cells of an early stage brain tumor and in cells at the periphery of a terminal stage brain tumor of a mouse model of malignant astrocytoma. The aims of the proposed project include genetic strategies to induce and directly visualize tumor development in the brains of mice, immunohistochemistry to describe the expression of Ascl1 in tumors at multiple stages of development, and use of fluorescence activated cell sorting (FACS) to isolate and characterize the tumorigenic properties of Ascl1-expressing tumor cells in vitro and in vivo. Finally, the requirement for Ascl1 for tumor formation and progression in this mouse model of glioma will be directly tested by conditional deletion of Ascl1. The culmination of this study will provide new insights into the heterogeneity and molecular mechanisms of glioma tumors.