miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma
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 th...
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724015225 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Enrico Pozzo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6c789bd664d445469e5a2489c7cb0b99 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-6c789bd664d445469e5a2489c7cb0b992025-01-13T04:18:46ZengElsevierCell Reports2211-12472025-01-01441115171miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcomaEnrico Pozzo0Laura Yedigaryan1Nefele Giarratana2Chao-chi Wang3Gabriel Miró Garrido4Ewoud Degreef5Vittoria Marini6Gianmarco Rinaldi7Bernard K. van der Veer8Gabriele Sassi9Guy Eelen10Mélanie Planque11Alessandro Fanzani12Kian Peng Koh13Peter Carmeliet14Jason T. Yustein15Sarah-Maria Fendt16Anne Uyttebroeck17Maurilio Sampaolesi18Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Corresponding authorTranslational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumLaboratory 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, BelgiumLaboratory of Stem Cell and Developmental Epigenetics, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumTranslational 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, BelgiumLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, 3000 Leuven, BelgiumLaboratory 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, BelgiumDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyLaboratory of Stem Cell and Developmental Epigenetics, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumLaboratory 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, DenmarkAflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, USALaboratory 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, BelgiumDepartment of Pediatric Hemato-Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, BelgiumTranslational 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124724015225CP: Cancer |
| spellingShingle | 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 miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma Cell Reports CP: Cancer |
| title | miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma |
| title_full | miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma |
| title_fullStr | miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma |
| title_full_unstemmed | miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma |
| title_short | miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma |
| title_sort | mir 449a mir 340 reprogram cell identity and metabolism in fusion negative rhabdomyosarcoma |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724015225 |
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