Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility
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, , is toxic or unstable in most primary tissues. Consequently, attempts to model Ewing sarcomagenesis have proven unsuc...
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| Published in: | Cancers Vol. 12; no. 4; p. 948 |
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| Main Authors: | , , , , , |
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| 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,
, 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. |
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| AbstractList | 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. 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, , 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. 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. |
| Author | Bishop, Alexander J R Lawrence, Liesl A Iskra, Brian S Bassani, Nicklas Miller, Henry E Gorthi, Aparna |
| AuthorAffiliation | 2 Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA 1 Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USA; millerh1@livemail.uthscsa.edu (H.E.M.) |
| AuthorAffiliation_xml | – name: 1 Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USA; millerh1@livemail.uthscsa.edu (H.E.M.) – name: 2 Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA |
| Author_xml | – sequence: 1 givenname: Henry E orcidid: 0000-0003-3756-3918 surname: Miller fullname: Miller, Henry E organization: Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA – sequence: 2 givenname: Aparna surname: Gorthi fullname: Gorthi, Aparna organization: Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA – sequence: 3 givenname: Nicklas surname: Bassani fullname: Bassani, Nicklas organization: Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA – sequence: 4 givenname: Liesl A surname: Lawrence fullname: Lawrence, Liesl A organization: Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA – sequence: 5 givenname: Brian S surname: Iskra fullname: Iskra, Brian S organization: Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA – sequence: 6 givenname: Alexander J R orcidid: 0000-0002-5742-4387 surname: Bishop fullname: Bishop, Alexander J R organization: Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USA |
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| Keywords | developmental trajectories Ewing sarcoma replication stress cell identity transcriptomics R-loops single cell biology EWSR1-FLI1 sarcomagenesis manifold learning |
| Language | English |
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