EPCO-02. HIGH CELLULAR PLASTICITY STATE OF HUMAN MEDULLOBLASTOMA LOCAL RECURRENCE AND DISTANT DISSEMINATION

Abstract Medulloblastoma (MB) is a heterogeneous pediatric brain tumor with variable clinical outcomes. Since current treatments facing limitations due to tumor resistance, less than 10% of relapsed patients survive beyond five years, with poorly understood recurrence mechanisms. To obtain cellular diversity and genetic characters in primary and recurrent MB, we conducted comprehensive analyses utilizing the single-cell/nucleus RNA sequencing (sc/snRNA-seq), snATAC-seq and spatial transcriptomics, complemented with bulk RNA sequencing and matched primary-recurrent whole exon profiles. SHH and Group_3 subgroups revealed distinct cellular subsets, including cycling, differentiated and quiescent tumor cells. Recurrent or disseminated MB displayed a dramatically different cellular ecosystem compared to primary tumors, with varying proportions of shared cell types. Local recurrence exhibited a higher enrichment of cycling tumor cells, while differentiated subset was notably present in disseminated lesions, indicating that local recurrences harbored the stronger proliferative capacity, whereas disseminations relatively well differentiated. Additionally, chromosomal alterations were assessed, reflecting distinct genetic subclones, such as chr7q gain and chr11 loss in Group_3 disseminations. Notably, the emergence of a subpopulation termed “high cellular plasticity (HCP)” during MB progression was noted, characterized by dynamic adaptability and stemness properties. As validated, HCP state was associated with increased chromatin accessibility, contributing to tumor recurrence and immune microenvironment remodeling. Functionally, inhibiting markers associated with HCP cells, such as PTPRZ1, efficiently suppressed MB metastasis in preclinical models. In conclusion, our findings fill the critical knowledge gaps in understanding the cellular diversity, chromosomal alterations and biological dynamics in MB recurrence and dissemination, offering potential therapeutic interventions.