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, 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Cancers - 12(2020), 4 vom: 11. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Miller, Henry E [VerfasserIn] |
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| Links: |
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| Themen: |
Cell identity |
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| Anmerkungen: |
Date Revised 28.12.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3390/cancers12040948 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308754158 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Ewing sarcoma | |
| 650 | 4 | |a R-loops | |
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| 650 | 4 | |a developmental trajectories | |
| 650 | 4 | |a manifold learning | |
| 650 | 4 | |a replication stress | |
| 650 | 4 | |a sarcomagenesis | |
| 650 | 4 | |a single cell biology | |
| 650 | 4 | |a transcriptomics | |
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| 700 | 1 | |a Bassani, Nicklas |e verfasserin |4 aut | |
| 700 | 1 | |a Lawrence, Liesl A |e verfasserin |4 aut | |
| 700 | 1 | |a Iskra, Brian S |e verfasserin |4 aut | |
| 700 | 1 | |a Bishop, Alexander J R |e verfasserin |4 aut | |
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