Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 11, 2020
- Source ID
- 10.3390/cancers12040948
Entities
People
- Alexander J R Bishop
- Aparna Gorthi
- Brian S. Iskra
- Henry E Miller
- Liesl A Lawrence
- Nicklas Bassani
Organizations
- Cancer Prevention and Research Institute of Texas
- Congressionally Directed Medical Research Programs
- National Cancer Institute
- National Center for Advancing Translational Sciences
- National Institute on Aging
- National Institutes of Health Clinical Center