| Title: |
Modelling EWS::FLI1 protein fluctuations reveal determinants of tumor plasticity in Ewing sarcoma |
| Authors: |
Veveeyan Suresh; Christoph Hafemeister; Andri Konstantinou; Sarah Grissenberger; Caterina Sturtzel; Martha M Zylka; Florencia Cidre-Aranaz; Andrea Wenninger-Weinzierl; Karla Queiroz; Dorota Kurek; Martin Distel; Anna Obenauf; Thomas G P Grünewald; Florian Halbritter; Heinrich Kovar; Valerie Fock |
| Source: |
EMBO Molecular Medicine, Vol 18, Iss 2, Pp 646-676 (2026) |
| Publisher Information: |
Springer Nature, 2026. |
| Publication Year: |
2026 |
| Collection: |
LCC:Medicine (General); LCC:Genetics |
| Subject Terms: |
Epithelial Mesenchymal Plasticity; Ewing Sarcoma; EWS::FLI1; Metastasis; Oncogene Fluctuation; Medicine (General); R5-920; Genetics; QH426-470 |
| Description: |
Abstract Tumor cell plasticity drives metastasis and therapy resistance, yet its regulation by oncoprotein dosage dynamics remains poorly understood. In Ewing sarcoma (EwS), variations in EWS::FLI1 (EF) fusion oncoprotein activity have been associated with epithelial-mesenchymal plasticity (EMP). Using degron technology, we precisely modulated endogenous EF in EwS cells and linked phenotypic states to distinct oncoprotein dosages. Strikingly, modest EF depletion promoted a pro-metastatic phenotype that diminished upon near-complete EF loss, revealing a paradoxical effect of submaximal EF inhibition. Nascent RNA-sequencing uncovered distinct gene clusters with heterogenous transcriptional responses to graded EF loss. Genes most sensitive to subtle EF depletion harbored GGAA microsatellites within EF-bound enhancers, while chromatin profiling uncovered candidate cofactors regulating EF-repressed EMP programs. Transient EF depletion followed by rapid restoration, modelling oncoprotein fluctuations, caused persistent dysregulation of genes functionally linked to enhanced extravasation and metastatic burden in preclinical models. This study highlights the therapeutic challenge of incomplete EF elimination, serving a paradigm in which oncoprotein dosage dynamics act as non-genetic drivers of disease progression and reveal novel vulnerabilities of advanced disease. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1757-4684 |
| Relation: |
https://doaj.org/toc/1757-4684 |
| DOI: |
10.1038/s44321-025-00364-7 |
| Access URL: |
https://doaj.org/article/c3e53569995b4a00a026dd1be6cacb0e |
| Accession Number: |
edsdoj.3e53569995b4a00a026dd1be6cacb0e |
| Database: |
Directory of Open Access Journals |