Reconstruction of ewing sarcoma developmental context from mass-scale transcriptomics reveals characteristics of ewsr1-fli1 permissibility

Henry E. Miller, Aparna Gorthi, Nicklas Bassani, Liesl A. Lawrence, Brian S. Iskra, Alexander J.R. Bishop

Producción científica: Articlerevisión exhaustiva

19 Citas (Scopus)

Resumen

Ewing sarcoma is an aggressive pediatric cancer of enigmatic cellular origins typically resulting from a single translocation event t (11; 22) (q24; q12). The resulting fusion gene, EWSR1-FLI1, is toxic or unstable in most primary tissues. Consequently, attempts to model Ewing sarcomagenesis have proven unsuccessful thus far, highlighting the need to identify the cellular features which permit stable EWSR1-FLI1 expression. By re-analyzing publicly available RNA-Sequencing data with manifold learning techniques, we uncovered a group of Ewing-like tissues belonging to a developmental trajectory between pluripotent, neuroectodermal, and mesodermal cell states. Furthermore, we demonstrated that EWSR1-FLI1 expression levels control the activation of these developmental trajectories within Ewing sarcoma cells. Subsequent analysis and experimental validation demonstrated that the capability to resolve R-loops and mitigate replication stress are probable prerequisites for stable EWSR1-FLI1 expression in primary tissues. Taken together, our results demonstrate how EWSR1-FLI1 hijacks developmental gene programs and advances our understanding of Ewing sarcomagenesis.

Idioma originalEnglish (US)
Número de artículo948
PublicaciónCancers
Volumen12
N.º4
DOI
EstadoPublished - abr 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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