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Article

Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility

1
Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USA
2
Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(4), 948; https://doi.org/10.3390/cancers12040948
Received: 29 March 2020 / Revised: 9 April 2020 / Accepted: 10 April 2020 / Published: 11 April 2020
(This article belongs to the Special Issue Ewing Sarcoma)
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. View Full-Text
Keywords: Ewing sarcoma; EWSR1-FLI1; transcriptomics; manifold learning; single cell biology; R-loops; replication stress; sarcomagenesis; developmental trajectories; cell identity Ewing sarcoma; EWSR1-FLI1; transcriptomics; manifold learning; single cell biology; R-loops; replication stress; sarcomagenesis; developmental trajectories; cell identity
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MDPI and ACS Style

Miller, H.E.; Gorthi, A.; Bassani, N.; Lawrence, L.A.; Iskra, B.S.; Bishop, A.J.R. Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility. Cancers 2020, 12, 948. https://doi.org/10.3390/cancers12040948

AMA Style

Miller HE, Gorthi A, Bassani N, Lawrence LA, Iskra BS, Bishop AJR. Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility. Cancers. 2020; 12(4):948. https://doi.org/10.3390/cancers12040948

Chicago/Turabian Style

Miller, Henry E., Aparna Gorthi, Nicklas Bassani, Liesl A. Lawrence, Brian S. Iskra, and Alexander J.R. Bishop. 2020. "Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility" Cancers 12, no. 4: 948. https://doi.org/10.3390/cancers12040948

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