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Updated: Sep 21, 2025
09:58
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
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EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma.
April A Apfelbaum1,2, Feinan Wu3, Allegra G Hawkins4
1Cancer Biology PhD Program, University of Michigan, Ann Arbor, Michigan.
Summary
HOXD13 influences Ewing sarcoma progression by modulating EWS::FLI1 activity. This developmental factor activates repressed genes, promoting mesenchymal phenotypes and tumor cell states.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ewing sarcoma propagation depends on precise EWS::FLI1 transcriptional regulation.
- Understanding fusion regulation mechanisms is key to advancing tumor progression insights.
Purpose of the Study:
- Investigate HOXD13's influence on EWS::FLI1 transcriptional activity.
- Determine HOXD13's role in Ewing sarcoma metastatic phenotypes.
Main Methods:
- Utilized tumor and cell line datasets to define EWS::FLI1 binding sites and targets.
- Employed ChIP, CRISPR interference, CUT&RUN, and RNA sequencing.
- Analyzed transcriptional states via bulk and single-cell transcriptomics; assessed mesenchymal phenotypes.
Main Results:
- EWS::FLI1 creates a de novo GGAA microsatellite enhancer at the HOXD locus.
- HOXD13 knockdown altered developmental gene programs and EWS::FLI1 targets.
- HOXD13 activated EWS::FLI1-repressed genes, inducing mesenchymal and migratory states.
Conclusions:
- Ewing sarcoma tumors exhibit a mesenchymal transcriptional continuum.
- Competing activities of EWS::FLI1 and HOXD13 determine cell identity within this continuum.
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