PUBLICATION
Origin of Ewing sarcoma by embryonic reprogramming of neural crest to mesoderm
- Authors
- Vasileva, E., Arata, C., Luo, Y., Burgos, R., Crump, J.G., Amatruda, J.F.
- ID
- ZDB-PUB-251011-10
- Date
- 2025
- Source
- Cell Reports : 116376116376 (Journal)
- Registered Authors
- Amatruda, James F., Crump, Gage DeKoeyer, Vasileva, Elena
- Keywords
- CP: Cancer, CP: Developmental biology, ETS factors, Ewing sarcoma, cell reprogramming, development, fin development, mesoderm, neural crest cells, pediatric oncology, single-cell analysis, zebrafish genetic models
- Datasets
- GEO:GSE280398, GEO:GSE306234
- MeSH Terms
-
- Animals
- Cellular Reprogramming*
- Humans
- Mesoderm*/embryology
- Mesoderm*/metabolism
- Mesoderm*/pathology
- Neural Crest*/embryology
- Neural Crest*/metabolism
- Neural Crest*/pathology
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Proto-Oncogene Protein c-fli-1/genetics
- Proto-Oncogene Protein c-fli-1/metabolism
- RNA-Binding Protein EWS/genetics
- RNA-Binding Protein EWS/metabolism
- Sarcoma, Ewing*/genetics
- Sarcoma, Ewing*/metabolism
- Sarcoma, Ewing*/pathology
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 41072418 Full text @ Cell Rep.
Citation
Vasileva, E., Arata, C., Luo, Y., Burgos, R., Crump, J.G., Amatruda, J.F. (2025) Origin of Ewing sarcoma by embryonic reprogramming of neural crest to mesoderm. Cell Reports. :116376116376.
Abstract
Ewing sarcoma is a malignant small round blue cell tumor caused by chromosomal translocations that generate aberrant fusion oncogenes, most frequently EWSR1::FLI1. The cell of origin and mechanisms of EWSR1::FLI1-driven transformation have remained unresolved, largely due to the lack of a representative animal model. Using a zebrafish genetic Ewing sarcoma model, we provide evidence for a neural crest origin of this cancer. Neural crest-derived cells uniquely tolerate expression of EWSR1::FLI1, and targeted expression of EWSR1::FLI1 in these cells generates lethal Ewing sarcomas. Single-cell analysis of tumor initiation shows that EWSR1::FLI1 reprograms neural crest-derived cells to a mesoderm-like state, strikingly resulting in ectopic fins throughout the body. By profiling chromatin accessibility and genome-wide EWSR1::FLI1 binding, we find that the fusion oncogene hijacks developmental enhancers for neural crest to mesoderm reprogramming during cancer initiation. These findings show how a single mutation profoundly alters embryonic cell fate decisions to initiate a devastating childhood cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping