Abstract Resolving the molecular mechanisms driving childhood brain tumors will uncover tumor-specific vulnerabilities and advance mechanism-of-action-based therapies. Here we describe a continuum of cell-states in Group 3/4 medulloblastomas, the most frequent and fatal cerebellar embryonal tumor subgroups, based on the differential activity of transcription-factor-driven gene networks derived using a comprehensive single-nucleus multi-omic medulloblastoma atlas. We show that Group 3/4 tumor diversity stems from enriched cell-states along four molecular identity axes: photoreceptor, MYC, precursor, and unipolar brush cell-like. We identified a potential role of PAX6 in driving dual Group 3- and Group 4-like tumor trajectories in subtype VII tumors. Our study demonstrates how oncogenic events together with lineage determinants drive Group 3/4 tumor identity away from their original source in the cerebellar unipolar brush cell lineage.

Gene regulatory network landscape of Group 3/4 medulloblastoma