Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma PMID: 40664627

ADC Targets in Oncology

2026-04-10

Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma

Nat Commun. 2025 Jul 16;16(1):6537. doi: 10.1038/s41467-025-61725-x.

Bartimée Galvan ¹ ² , Loïc Ongena ¹ , Jonathan Bruyr ¹ , Gregory Fettweis ¹ ³ , Eva Lucarelli ¹ , Arnaud Lavergne ⁴ , Emeline Mariavelle ¹ , Tina M O'Grady ¹ ⁵ , Zahrat El Oula Hassoun ¹ ⁶ , Margaux Claes ¹ , Laurence Dubois ¹ , Kevin A W Lee ⁷ , Véronique Kruys ⁸ , Cyril Gueydan ⁸ , Jules Durand ⁹ ¹⁰ , Eric Hervouet ⁹ ¹⁰ , Florian H Geyer ¹¹ ¹² ¹³ , Ana Banito ¹¹ ¹⁴ , Roland Imle ¹¹ ¹⁴ ¹⁵ , Lianghao Mao ¹¹ ¹² ¹⁶ , Ashok K Jayavelu ¹¹ ¹² ¹⁶ , Thomas G P Grünewald ¹¹ ¹² ¹³ ¹⁷ , Florencia Cidre-Aranaz ¹¹ ¹² ¹³ , Jean-Claude Twizere ¹⁸ , Franck Dequiedt ¹⁹

Affiliations

1. Laboratory of Gene Expression and Cancer, GIGA Institute, University of Liège (ULiège), Liège, Belgium.
2. Division of Oncology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
3. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, USA.
4. Genomics Platform, GIGA Institute, University of Liège (ULiège), Liège, Belgium.
5. Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, USA.
6. Department of Integrative Structural and Computational Biology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, USA.
7. Division of Life Science, The Hong Kong University of Sci. & Tech, Clear Water Bay, Kowloon, Hong Kong SAR, China.
8. Laboratory of Molecular Biology of the Gene, Department of Molecular Biology, Free University of Brussels (ULB), 6041, Gosselies, Belgium.
9. Université Franche-Comté, INSERM, EFS BFC, UMR1098, « Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique », F-25000, Besançon, France.
10. EPIGENExp platform, Université Franche-Comté, F-25000, Besançon, France.
11. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
12. National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
13. Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
14. Soft-Tissue Sarcoma research group (B380), German Cancer Research Center (DKFZ), Heidelberg, Germany.
15. Department of pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
16. Research Group Proteomics and Cancer Cell Signaling, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
17. Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
18. Laboratory of Viral Interactomes Networks, GIGA Institute, University of Liège (ULiège), 4000, Liège, Belgium.
19. Laboratory of Gene Expression and Cancer, GIGA Institute, University of Liège (ULiège), Liège, Belgium. [email protected].

Abstract

Many cancers are defined by gene fusions that frequently encode oncogenic transcription factors (TFs), such as EWSR1::FLI1 in Ewing sarcoma (EwS). Here, we report that independently to its canonical roles in transcription, EWSR1::FLI1 also functions as an mRNA decay factor, reshaping mRNA stability in EwS. This function participates in EWSR1::FLI1 tumorigenicity and involves interactions of EWSR1::FLI1 with the CCR4-NOT deadenylation complex via its EWSR1-derived low-complexity domain and with the RNA-binding protein HuR/ELAVL1 via its FLI1-derived region. Strikingly, we find that EWSR1::FLI1-mediated mRNA decay antagonizes the normal mRNA protective function of HuR and renders EwS cells highly sensitive to HuR inhibition. Our findings uncover a post-transcriptional function of EWSR1::FLI1 and suggest that targeting mRNA stability mechanisms may offer therapeutic opportunities for EwS.