Origin of Ewing sarcoma by embryonic reprogramming of neural crest to mesoderm.

Autor:	Vasileva E; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027 USA., Arata C; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Luo Y; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027 USA., Burgos R; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027 USA., Crump JG; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Amatruda JF; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027 USA.; Departments of Pediatrics and Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 29. Date of Electronic Publication: 2024 Oct 29.
DOI:	10.1101/2024.10.27.620438
Abstrakt:	Ewing sarcoma is a malignant small round blue cell tumor of bones and soft tissues 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 lack of a representative animal model. By developing a zebrafish 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 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. Competing Interests: Competing Interests The authors declare no competing interests.
Databáze:	MEDLINE
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