Language

English

Publication Date

1-21-2025

Journal

Cell Report Medicine

DOI

10.1016/j.xcrm.2024.101914

PMID

39809264

PMCID

PMC11866544

PubMedCentral® Posted Date

1-13-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Medulloblastoma, Humans, Neoplasm Recurrence, Local, Cell Plasticity, Cerebellar Neoplasms, Animals, Cell Line, Tumor, Chromatin, Mice, Single-Cell Analysis, Gene Expression Regulation, Neoplastic, medulloblastoma, recurrence and dissemination, cellular plasticity, PTPRZ1

Published Open-Access

yes

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