MODL-45. UNDERSTANDING OLIGODENDROCYTE PROGENITOR CELL CONTRIBUTION TO GLIOMAGENESIS USING A NOVEL PHARMACOGENETIC ABLATION TOOL

Abstract

Abstract In the central nervous system (CNS), gliomas represent almost 50% of all pediatric tumors and due to their complex histological and biological heterogeneity, aggressive standard treatment consisting of surgery and chemoradiotherapy remains ineffective. As a result, more biologically based therapies are urgently needed and this requires a deeper knowledge of the etiology and biology of gliomas, which can arise from oligodendrocyte progenitor cells (OPCs). OPCs are the most proliferative cell type in the CNS, and upon oncogenic mutations in OPCs, they exhibit defective asymmetric divisions with a concomitant increase in symmetrical renewal, leading to aberrant growth of OPCs prior to malignancy. Although OPC-like cells frequently found in human glioma significantly contribute to tumor heterogeneity and malignancy, how resident tumor-infiltrating OPCs functionally integrate into the tumor cell networks within the tumor microenvironment remains unknown. However, in order to address this critical gap in knowledge of the field, a novel mouse model of conditional OPC ablation must be used to overcome methodological challenges of most current approaches that often result in partial and transient OPC ablation, which limits our understanding of long-term function of OPCs. Here, we have successfully developed a novel pharmacogenetic model of conditional OPC ablation, eliminating 98.6% of all OPCs throughout the mouse brain for up to 12 days post ablation. This novel mouse model of complete OPC ablation can be combined with intracranial injection of tumor cells in order to reveal the longitudinal and spatial functional roles and the necessity for resident OPCs in the tumor context. Understanding the OPC-tumor cell crosstalk by using our state-of-the-art approach at both cellular and molecular levels will have significant clinical implications for improving treatment for patients with pediatric gliomas.