This study combines single-molecule microscopy and genome editing to characterize the dynamic behaviors of endogenous oncofusion transcription factor EWS::FLI1 in Ewing sarcoma cells. EWS::FLI1 forms...

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...

Abstract. Ewing Sarcoma (EwS) is a highly aggressive tumor arising in bones and soft tissues driven by the fusion oncoprotein EWSR1::FLI1. This aberrant transcription factor binds to GGAA microsatelli...

Oncogene - EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism

Oncogene - EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism

Ewing sarcoma (ES) is a bone and soft tissue sarcoma that is absolutely dependent on the EWS::FLI1 transcription factor for cell survival. No compound has been shown to reverse EWS::FLI1 activity in patients, and outcomes for relapsed patients remain poor. Trabectedin above a threshold concentration reverses the activity of EWS::FLI1 and is potentiated by low-dose irinotecan in vivo. This open-label phase 1/2 trial of trabectedin with irinotecan (SARC037) enrolled 37 relapsed/refractory patients with ES. The primary objectives were to determine the safety, tolerability, recommended phase 2 dose (RP2D; phase 1) and objective response rate (ORR; phase 2) of trabectedin administered as a 1-hour infusion in combination with low-dose irinotecan in patients with ES. The secondary objectives were to determine the progression-free survival (PFS), 6-month PFS, duration of response and 18F-fluorothymidine positron emission tomography (18F-FLT PET) avidity of ES tumors. The RP2D was trabectedin 1

The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deade...

Abstract. Over 90% of Ewing sarcomas (EWS) are driven by the EWS–FLI1 fusion oncoprotein. EWS–FLI1 acts as a pioneer transcription factor, altering the exp

Oncogene - Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma via aberrant expression of KCNN1/SK1 and dysregulation of calcium signaling

Deregulated transcription is a defining hallmark of cancer, especially pediatric malignancies, which are frequently driven by fusion transcription factors. Targeting transcription factors directly has...

Ewing sarcoma (EwS) is an aggressive, human-exclusive tumor typically driven by the EWS::FLI1 fusion protein. To assess whether the neomorphic functions of EWS::FLI1 are fundamentally dependent on evo...

The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deade...

Background Ewing sarcoma (ES), the second main pediatric bone sarcoma, is characterised by a chromosomal translocation leading to the formation of fusion proteins like EWS::FLI1. While several studies...

There are comments on PubPeer for publication: CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling (2016)

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