Abstract
Medulloblastoma (MB), a heterogeneous pediatric brain tumor, poses challenges in the treatment of tumor recurrence and dissemination. To characterize cellular diversity and genetic features, we comprehensively analyzed single-cell/nucleus RNA sequencing (sc/snRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and spatial transcriptomics profiles and identified distinct cellular populations in SHH (sonic hedgehog) and Group_3 subgroups, with varying proportions in local recurrence or dissemination. Local recurrence showed higher cycling tumor cell enrichment, whereas disseminated lesions had a relatively notable presence of differentiated subsets. Chromosomal alteration evaluation revealed distinct genetic subclones during MB progression, such as chr7q gain and chr11 loss in Group_3 disseminations. A subpopulation termed "high cellular plasticity (HCP)" emerged during MB progression and was associated with increased dividing potential and chromatin accessibility, contributing to recurrence. Inhibiting HCP-associated markers, like protein tyrosine phosphatase receptor type Z1 (PTPRZ1), efficiently suppressed MB progression in preclinical models. These findings address critical gaps in understanding the cellular diversity, chromosomal alterations, and biological dynamics of recurrent MB, offering potential therapeutic insights.