Language

English

Publication Date

6-1-2026

Journal

Experimental & Molecular Medicine

DOI

10.1038/s12276-026-01732-0

PMID

42249086

PMCID

PMC13323399

PubMedCentral® Posted Date

6-5-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Current treatment strategies for medulloblastoma remain ineffective owing to extensive tumor heterogeneity. We generated five platforms of omics data including liquid chromatography and mass spectrometry-based proteome and performed integrated multi-omic characterization to improve the conventional molecular classification of medulloblastoma. We identified seven refined distinct subtypes. The sonic hedgehog (SHH) group was reclassified into two subgroups, SHHα and SHHβ, whereas group 4 was divided into three subgroups, G4α, G4β, and G4γ. SHH and group 4 subtypes exhibit two distinct neuronal differentiation trajectories: granular neuron and unipolar brush cell differentiation (SHHβ and G4γ, respectively), both of which associated with more favorable clinical outcomes. Furthermore, we uncovered unique proteomic and kinomic properties that conferred increased treatment vulnerabilities to targeted therapeutic interventions against each of the three medulloblastoma subtypes associated with poor clinical outcomes. We demonstrated the therapeutic potential of exploiting these vulnerabilities by utilizing a proteasome inhibitor and subtype-specific agents, including CDK1/2, PARP, CLK1, and MET inhibitors. Mechanistic insights were further elucidated through in-depth proteome analyses. Our study qualifies the use of proteomic signatures and activation of neuronal differentiation trajectories to tailor selective therapeutic opportunities for distinct subgroups of patients with medulloblastoma.

Keywords

Medulloblastoma, Humans, Proteogenomics, Disease Progression, Proteome, Hedgehog Proteins, Cerebellar Neoplasms, Proteomics, Cell Differentiation, Animals

Published Open-Access

yes

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