miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Rhabdomyosarcoma (RMS) is a common pediatric soft tissue sarcoma originating in skeletal muscle.
• Fusion-negative RMS (FN-RMS) represents the majority of pediatric RMS cases and is characterized by an undifferentiated state.
• MicroRNAs (miRNAs) are key regulators of gene expression, influencing cell identity and function.

Purpose of the Study:

• To identify miRNAs that regulate the cell identity of fusion-negative rhabdomyosarcoma (FN-RMS).
• To investigate the downstream targets and functional consequences of identified miRNAs in FN-RMS.
• To explore the therapeutic potential of targeting specific metabolic pathways in FN-RMS.

Main Methods:

• Utilized miR-eCLIP technology to identify direct miRNA-mRNA interactions.
• Analyzed the impact of miRNAs on cell cycle and p53 signaling pathways.
• Investigated the role of the mitochondrial pyruvate carrier (MPC) complex in FN-RMS metabolism and progression.
• Assessed the effects of pharmacological MPC inhibition on FN-RMS cell behavior and metastatic potential.

Main Results:

• Identified miR-449a and miR-340 as critical regulators of FN-RMS cell identity, impacting cell cycle and p53 signaling.
• Demonstrated that miR-449a and miR-340 directly target transcripts involved in glycolysis and mitochondrial pyruvate transport, inhibiting the MPC complex.
• Showed that pharmacological inhibition of MPC induces a metabolic shift, reduces metastatic potential, and promotes cell cycle exit in FN-RMS cells.

Conclusions:

• miR-449a and miR-340 play a significant role in orchestrating FN-RMS cell identity.
• Inhibition of the mitochondrial pyruvate carrier (MPC) represents a promising therapeutic strategy to induce a quiescent, non-tumorigenic state in FN-RMS cells.