miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma
- Cell Rep. 2025 Jan 28;44(1):115171. doi: 10.1016/j.celrep.2024.115171.
- 1. Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: [email protected].
- 2. Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
- 3. Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.
- 4. Laboratory of Stem Cell and Developmental Epigenetics, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
- 5. Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Clinical and Experimental Endocrinology (CEE), KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
- 6. Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium.
- 7. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
- 8. Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates; Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
- 9. Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, USA.
- 10. Department of Pediatric Hemato-Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
- 11. Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Histology and Medical Embryology Unit, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy. Electronic address: [email protected].
Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, arises in skeletal muscle and remains in an undifferentiated state due to transcriptional and post-transcriptional regulators. Among its subtypes, fusion-negative RMS (FN-RMS) accounts for the majority of diagnoses in the pediatric population. MicroRNAs (miRNAs) are non-coding RNAs that modulate cell identity via post-transcriptional regulation of messenger RNAs (mRNAs). In this study, we identify miRNAs impacting FN-RMS cell identity, revealing miR-449a and miR-340 as major regulators of the cell cycle and p53 signaling. Through miR-eCLIP technology, we demonstrate that miR-449a and miR-340 directly target transcripts involved in glycolysis and mitochondrial pyruvate transport, inhibiting the mitochondrial pyruvate carrier (MPC) complex. Pharmacological MPC inhibition induces a similar metabolic shift, reducing metastatic potential and leading to cell cycle exit. Overall, miR-449 and miR-340 orchestrate FN-RMS cell identity, positioning MPC inhibition as a strategy to shift FN-RMS cells toward a non-tumorigenic, quiescent state.