2. Academic Validation
  3. miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma

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.
Enrico Pozzo 1,  Laura Yedigaryan 2,  Nefele Giarratana 2,  Chao-Chi Wang 2,  Gabriel Miró Garrido 2,  Ewoud Degreef 2,  Vittoria Marini 2,  Gianmarco Rinaldi 3,  Bernard K van der Veer 4,  Gabriele Sassi 5,  Guy Eelen 6,  Mélanie Planque 3,  Alessandro Fanzani 7,  Kian Peng Koh 4,  Peter Carmeliet 8,  Jason T Yustein 9,  Sarah-Maria Fendt 3,  Anne Uyttebroeck 10,  Maurilio Sampaolesi 11
Affiliations

Affiliations

  • 1 Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: enrico.pozzo@kuleuven.be.
  • 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: maurilio.sampaolesi@kuleuven.be.
PMID: 39799567 DOI: 10.1016/j.celrep.2024.115171
Abstract

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.

Keywords

CP: Cancer; UK-5099; cell identity; metabolism; miRNAs; mitochondrial pyruvate carrier; pediatric cancer; rhabdomyosarcoma.

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