A logical model of Ewing sarcoma cell epithelial‐to‐mesenchymal transition supports the existence of hybrid cellular phenotypes

Ewing sarcoma (ES) is a highly aggressive pediatric tumor driven by the RNA‐binding protein EWS (EWS)/friend leukemia integration 1 transcription factor (FLI1) chimeric transcription factor, which is involved in epithelial–mesenchymal transition (EMT). EMT stabilizes a hybrid cell state, boosting metastatic potential and drug resistance. Nevertheless, the mechanisms underlying the maintenance of this hybrid phenotype in ES remain elusive. Our study proposes a logical EMT model for ES, highlighting zinc finger E‐box‐binding homeobox 2 (ZEB2), miR‐145, and miR‐200 circuits that maintain hybrid states. The model aligns with experimental findings and reveals a previously unknown circuit supporting the mesenchymal phenotype. These insights emphasize the role of ZEB2 in the maintenance of the hybrid state in ES.