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, <i>EWSR1-FLI1</i>, is toxic or unstable in most primary tissues. Consequently, attempts to model Ewing sar...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/948 |
| _version_ | 1797570890361208832 |
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| author | Henry E. Miller Aparna Gorthi Nicklas Bassani Liesl A. Lawrence Brian S. Iskra Alexander J. R. Bishop |
| author_facet | Henry E. Miller Aparna Gorthi Nicklas Bassani Liesl A. Lawrence Brian S. Iskra Alexander J. R. Bishop |
| author_sort | Henry E. Miller |
| collection | DOAJ |
| description | 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, <i>EWSR1-FLI1</i>, 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. |
| first_indexed | 2024-03-10T20:31:51Z |
| format | Article |
| id | doaj.art-4f8985b546884b24b496935f57ab64cf |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:31:51Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4f8985b546884b24b496935f57ab64cf2023-11-19T21:20:40ZengMDPI AGCancers2072-66942020-04-0112494810.3390/cancers12040948Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 PermissibilityHenry E. Miller0Aparna Gorthi1Nicklas Bassani2Liesl A. Lawrence3Brian S. Iskra4Alexander J. R. Bishop5Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USADepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USAGreehey Children’s Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX 78229, USADepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USADepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USADepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USAEwing 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, <i>EWSR1-FLI1</i>, 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.https://www.mdpi.com/2072-6694/12/4/948Ewing sarcomaEWSR1-FLI1transcriptomicsmanifold learningsingle cell biologyR-loops |
| spellingShingle | Henry E. Miller Aparna Gorthi Nicklas Bassani Liesl A. Lawrence Brian S. Iskra Alexander J. R. Bishop Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility Cancers Ewing sarcoma EWSR1-FLI1 transcriptomics manifold learning single cell biology R-loops |
| title | Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility |
| title_full | Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility |
| title_fullStr | Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility |
| title_full_unstemmed | Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility |
| title_short | Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility |
| title_sort | reconstruction of ewing sarcoma developmental context from mass scale transcriptomics reveals characteristics of ewsr1 fli1 permissibility |
| topic | Ewing sarcoma EWSR1-FLI1 transcriptomics manifold learning single cell biology R-loops |
| url | https://www.mdpi.com/2072-6694/12/4/948 |
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