miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma
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.
Authors
- Guy Eelen (ORCID: https://orcid.org/0000-0003-3354-5819)
- Mélanie Planque (ORCID: https://orcid.org/0000-0001-7052-7084)
- Alessandro Fanzani (ORCID: https://orcid.org/0000-0001-7475-2668)
- Gabriel Miró Garrido
- Bernard K. van der Veer (ORCID: https://orcid.org/0000-0002-2576-7529)
- Kian Peng Koh (ORCID: https://orcid.org/0000-0003-2523-5175)
- Gianmarco Rinaldi (ORCID: https://orcid.org/0000-0001-5191-4580)
- Chao-chi Wang
- Sarah‐Maria Fendt (ORCID: https://orcid.org/0000-0001-6018-9296)
- Peter Carmeliet (ORCID: https://orcid.org/0000-0001-7961-1821)
- Ewoud Degreef
- Vittoria Marini (ORCID: https://orcid.org/0000-0002-0504-8682)
- Enrico Pozzo (ORCID: https://orcid.org/0000-0002-3362-3509)
- Laura Yedigaryan (ORCID: https://orcid.org/0000-0002-1701-9109)
- Nefele Giarratana (ORCID: https://orcid.org/0000-0002-8143-6230)
- Anne Uyttebroeck (ORCID: https://orcid.org/0000-0001-5644-424X)
- Gabriele Sassi (ORCID: https://orcid.org/0000-0002-7921-2764)
- Maurilio Sampaolesi (ORCID: https://orcid.org/0000-0002-2422-3757)
- Jason T. Yustein (ORCID: https://orcid.org/0000-0002-2052-0527)
Institutions
- Emory University (US)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Center for Cancer and Blood Disorders (US)
- Aflac (United States) (US)
- University of Brescia (IT)
- KU Leuven (BE)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.115171
- Citations
- 2
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.87