miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma
Enrico Pozzo,
Laura Yedigaryan,
Nefele Giarratana,
Chao-chi Wang,
Gabriel Miró Garrido,
Ewoud Degreef,
Vittoria Marini,
Gianmarco Rinaldi,
Bernard K. van der Veer,
Gabriele Sassi,
Guy Eelen,
Mélanie Planque,
Alessandro Fanzani,
Kian Peng Koh,
Peter Carmeliet,
Jason T. Yustein,
Sarah-Maria Fendt,
Anne Uyttebroeck,
Maurilio Sampaolesi
Affiliations
Enrico Pozzo
Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Corresponding author
Laura Yedigaryan
Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Nefele Giarratana
Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Chao-chi Wang
Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Gabriel Miró Garrido
Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Ewoud Degreef
Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Vittoria Marini
Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Gianmarco Rinaldi
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
Bernard K. van der Veer
Laboratory of Stem Cell and Developmental Epigenetics, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Gabriele Sassi
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
Guy Eelen
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
Mélanie Planque
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
Alessandro Fanzani
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
Kian Peng Koh
Laboratory of Stem Cell and Developmental Epigenetics, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Peter Carmeliet
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
Jason T. Yustein
Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, USA
Sarah-Maria Fendt
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
Anne Uyttebroeck
Department of Pediatric Hemato-Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
Maurilio Sampaolesi
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; Corresponding author
Summary: 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.
