DMG-11. Decoding Ets Transcription Factors Role in Pediatric High-Grade Glioma Heterogeneity

Abstract Pediatric gliomas are the most prevalent malignant brain tumors in children, accounting for nearly half of all diagnoses and serving as a leading cause of cancer-related mortality in those aged 0–14 years. Despite aggressive standard of care which involve surgery, radiation, and chemotherapy, the prognosis for high-grade pediatric gliomas remains poor, with a 5-year survival rate of approximately 25%. Additionally, survivors often suffer significant cognitive impairments and reduced quality of life due to the intensive impact of these therapies on the developing brain. These challenges highlight the urgent need for alternative therapeutic approaches and a deeper understanding of tumor biology. Using a cutting-edge, non-invasive postnatal electroporation model (MADR) and a comprehensive genomic profiling, we identified members of the ETS transcription factor family as pivotal drivers in pediatric gliomagenesis. These proteins, which regulate critical cellular activities such as proliferation and differentiation, include oncogenic subfamilies like Pea3 (ETV1, ETV4, ETV5) and ETV6 (aka Tel). Among these, evidence suggest ETV5 plays a crucial role in glial lineage specification by influencing neural precursor cells to adopt an oligodendrocyte progenitor cell (OPC)-like phenotype, a highly proliferative and migratory population believed to serve as glioma-initiating cells. Our findings demonstrate that ETV5 and other ETS factors are significantly upregulated in pediatric gliomas and drives tumor development by reciprocal cross-talk with glial-specific transcriptional networks, including OLIG2. In vivo disruption of ETV5 markedly inhibits tumor growth, delays progression, and improves survival, highlighting its central role in glioma biology. Furthermore, ongoing investigations analyzing single-cell data from inducible MADR tumor models have unveiled the complex interplay between ETV1, ETV4, ETV5, and ETV6, offering further insights into their specific contributions to tumor cell fate determination and gene regulatory networks in glioma. This research underscores the fundamental role of ETS factors in glioma heterogeneity.