Abstract BACKGROUND Pediatric gliomas are the most common form of malignant brain tumors in children, representing nearly 50% of all pediatric brain tumor cases and standing as a primary cause of cancer-related deaths in individuals under the age of 15. Current Gold Standard treatments—consisting of surgical resection, radiotherapy, and chemotherapy—are aggressive but largely ineffective for high-grade gliomas, which have a poor 5-year survival rate of around 25%. Moreover, survivors frequently endure lasting cognitive deficits and diminished life quality due to the harsh impact of these interventions on the developing brain. These limitations underscore the pressing need for novel therapeutic strategies and a more comprehensive understanding of the disease’s molecular drivers and tumor behavior. MATERIAL AND METHODS To explore the molecular underpinnings of pediatric gliomagenesis, we utilized an advanced non-invasive postnatal electroporation approach (MADR) to create an inducible mouse model and derived organoids in combination with extensive genomic analyses. Through this platform, we identified several ETS transcription factors as key contributors to tumor development. These factors, including the Pea3 subfamily (ETV1, ETV4, ETV5) and ETV6 (also known as Tel), regulate essential cellular functions such as proliferation and cell differentiation shaping the tumor heterogeneity. RESULTS Our data reveal that ETV5, in particular, plays a vital role in glial fate decisions by promoting the differentiation of neural precursor cells toward an oligodendrocyte progenitor cell (OPC)-like phenotype. OPCs are highly proliferative and migratory cells considered potential origins of glioma. We observed significant and overexpression of ETV5 and other ETS factors in pediatric gliomas, where they interact directly and dynamically with glial-specific transcriptional regulators like OLIG2 to drive tumor formation. Targeted in vivo suppression of ETV5 resulted in substantial reductions in tumor growth, delayed disease progression, and improved survival outcomes, affirming its functional importance. Single-cell analyses of inducible MADR-derived organoids are further unraveling the common and different roles of ETV1, ETV4, ETV5, and ETV6 in determining the different tumor progression, cell identity, and how they regulate transcriptional programs during glioma genesis showing they importance of its regulations for the tumor success. CONCLUSION These findings emphasize the central involvement of ETS transcription factors in promoting glioma diversity and illustrate how the distinct activation of individual Ets family members can direct the lineage and functional state of tumor subpopulations. These findings position ETS factors as key regulators of tumor biology and promising therapeutic targets.
Fuentes-Fayos et al. (Wed,) studied this question.