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Proteomic profiling identifies key proteins, pathways and molecular subtypes regulating chemo-radio-sensitivity and relapse in rhabdomyosarcoma

ABSTRACT: Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, exhibits marked clinical heterogeneity driven by poorly understood molecular mechanisms. Identifying the molecular characteristics of different RMS subtypes and the molecular pathways influencing RMS treatment response and recurrence is an urgent clinical need. Here, we perform deep proteomic profiling of 19 RMS tumors (8 alveolar [ARMS], 11 embryonal [ERMS]) and matched normal tissues, integrating bioinformatics with functional validation to delineate subtype-specific pathways, therapy resistance drivers, and actionable targets. ARMS tumors are characterized by ubiquitination pathway activation (UBE2R2, UBE2J2), while ERMS exhibits spliceosome dysregulation. Chemo- and radio-resistant tumors both show significant enrichment in ribosome pathway. Relapsed cases show phosphonate and phosphinate metabolism pathway enrichment, suggesting metabolism reliance. Unsupervised clustering reveals ribosome- and glycolysis-driven subtypes with distinct metabolic dependencies. Functional studies implicate MED18—a core component of the Mediator complex—in mediating therapy resistance possibly via promoting DNA damage repair. Our study establishes proteomics as a tool to decode RMS heterogeneity, proposing subtype-tailored strategies targeting ubiquitination, splicing, and metabolism.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lu Wen

PROVIDER: PXD069421 | iProX | Tue Oct 14 00:00:00 BST 2025

REPOSITORIES: iProX

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Proteomic profiling identifies key proteins, pathways and molecular subtypes regulating chemo-radio-sensitivity and relapse in rhabdomyosarcoma

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