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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number948
JournalCancers
Volume12
Issue number4
DOIs
StatePublished - Apr 2020

Keywords

  • Cell identity
  • Developmental trajectories
  • EWSR1-FLI1
  • Ewing sarcoma
  • Manifold learning
  • R-loops
  • Replication stress
  • Sarcomagenesis
  • Single cell biology
  • Transcriptomics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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