Modelling EWS::FLI1 protein fluctuations reveal determinants of tumor plasticity in Ewing sarcoma

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

SUBMITTER: Veveeyan Suresh 

PROVIDER: S-SCDT-10_1038-S44321-025-00364-7 | biostudies-other |

REPOSITORIES: biostudies-other