BIOL-06. 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 and the tumor microenvironment. Oligodendrocyte progenitor cells (OPCs) are a potential origin of human gliomas (as suggested by studies in genetically engineered mouse models) and human OPC-like tumor cells contribute to tumor heterogeneity and malignancy. Resident (non-neoplastic) OPCs have been found to intermix with glioma cells and proliferate within the tumor microenvironment. The significance of the interactions of resident OPCs and glioma cells remains unknown. We hypothesize that resident OPCs functionally integrate into the tumor cell network and affect tumor properties. We have generated a novel mouse model of conditional OPC ablation 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 in our study, 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. In the future, we plan to combine the mouse model of complete OPC ablation with orthotopic glioma models 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.