Proteomic Profiling Reveals Candidate Proteins and Pathways Associated with Chemo-Radio-Sensitivity and Relapse in...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma.
• RMS presents significant clinical heterogeneity due to poorly understood molecular drivers.
• Identifying RMS subtype-specific molecular pathways is crucial for improving treatment response and reducing recurrence.

Purpose of the Study:

• To perform deep proteomic profiling of alveolar RMS (ARMS) and embryonal RMS (ERMS) tumors.
• To integrate bioinformatics and functional validation to identify subtype-specific pathways, therapy resistance mechanisms, and potential therapeutic targets.
• To decode RMS heterogeneity using proteomics for developing tailored treatment strategies.

Main Methods:

• Deep proteomic profiling of 19 RMS tumors (8 ARMS, 11 ERMS) and matched normal tissues.
• Bioinformatic analysis to delineate subtype-specific molecular pathways and resistance drivers.
• Functional validation studies to confirm the role of identified targets, such as MED18, in therapy resistance.

Main Results:

• ARMS tumors show activation of the ubiquitination pathway (UBE2R2, UBE2J2).
• ERMS tumors exhibit spliceosome dysregulation.
• Chemo- and radio-resistant tumors are enriched in the ribosome pathway; relapsed cases show enrichment in phosphonate and phosphinate metabolism.
• Unsupervised clustering identified ribosome- and glycolysis-driven subtypes with distinct metabolic dependencies.
• MED18 was implicated in mediating therapy resistance, potentially through DNA damage repair promotion.

Conclusions:

• Proteomics is a valuable tool for understanding RMS heterogeneity.
• Distinct molecular pathways (ubiquitination, splicing, metabolism) are associated with RMS subtypes and treatment outcomes.
• Subtype-tailored therapeutic strategies targeting these pathways are proposed for improved RMS management.