ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 30 citations in OpenAlex.
- Potential biomarkers of Ewing sarcoma identified through a Europe-wide analysis of prospectively collected samples.Scientific reports · 2026Article
- Molecular Characterization of Soft Tissue Sarcomas Using RNA-Based Next-Generation Sequencing.International journal of molecular sciences · 2026Article
- Modelling EWS::FLI1 protein fluctuations reveal determinants of tumor plasticity in Ewing sarcoma.EMBO molecular medicine · 2026Article
- Review
- Generation of Hoxa11-3XFLAG and Hoxd11-3XFLAG alleles to investigate Hox11 genome-wide binding.Developmental biology · 2025Article
- Selective Enhancer Dependencies in MYC-Intact and MYC-Rearranged Germinal Center B-cell Diffuse Large B-cell Lymphoma.Blood cancer discovery · 2025Article
- Mapping Knowledge Structure and Themes Trends of Ewing Sarcoma: A Text-Mining Study.Annals of surgical oncology · 2025Article
- Knockdown of HOXD13 in Oral Squamous Cell Carcinoma Inhibited its Proliferation, Migration, and Influenced Fatty Acid Metabolism.Journal of Cancer · 2025Article
- ETS1, a Target Gene of the EWSR1::FLI1 Fusion Oncoprotein, Regulates the Expression of the Focal Adhesion Protein TENSIN3.Molecular cancer research : MCR · 2024Article
- Human EWS-FLI protein levels and neomorphic functions show a complex, function-specific dose-response relationship inOpen biology · 2024Article
- Unlocking epigenetics for precision treatment of Ewing's sarcoma.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2024Article
- Pharmacological targeting of the cancer epigenome.Nature cancer · 2024Review
- CD99 Modulates the Proteomic Landscape of Ewing Sarcoma Cells and Related Extracellular Vesicles.International journal of molecular sciences · 2024Article
- ETS1, a target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3.bioRxiv : the preprint server for biology · 2023Article
- Cancer-Associated Fibroblast-Like Tumor Cells Remodel the Ewing Sarcoma Tumor Microenvironment.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma.International journal of molecular sciences · 2023Review
- Extracellular vesicle-associated IGF2BP3 tunes Ewing sarcoma cell migration and affects PI3K/Akt pathway in neighboring cells.Cancer gene therapy · 2023Article
- The CUT&RUN suspect list of problematic regions of the genome.Genome biology · 2023Article
- Carcinoma-associated fibroblast-like tumor cells remodel the Ewing sarcoma tumor microenvironment.bioRxiv : the preprint server for biology · 2023Article
- Article
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Authors and funding
17 authors at 8 institutions in 3 countries.
Funding
Abstract
purposePropagation of Ewing sarcoma requires precise regulation of EWS::FLI1 transcriptional activity. Determining the mechanisms of fusion regulation will advance our understanding of tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes Ewing sarcoma metastatic phenotypes, influences EWS::FLI1 transcriptional activity. EXPERIMENTAL
designExisting tumor and cell line datasets were used to define EWS::FLI1 binding sites and transcriptional targets. Chromatin immunoprecipitation and CRISPR interference were employed to identify enhancers. CUT&RUN and RNA sequencing defined binding sites and transcriptional targets of HOXD13. Transcriptional states were investigated using bulk and single-cell transcriptomic data from cell lines, patient-derived xenografts, and patient tumors. Mesenchymal phenotypes were assessed by gene set enrichment, flow cytometry, and migration assays.
resultsWe found that EWS::FLI1 creates a de novo GGAA microsatellite enhancer in a developmentally conserved regulatory region of the HOXD locus. Knockdown of HOXD13 led to widespread changes in expression of developmental gene programs and EWS::FLI1 targets. HOXD13 binding was enriched at established EWS::FLI1 binding sites where it influenced expression of EWS::FLI1-activated genes. More strikingly, HOXD13 bound and activated EWS::FLI1-repressed genes, leading to adoption of mesenchymal and migratory cell states that are normally suppressed by the fusion. Single-cell analysis confirmed that direct transcriptional antagonism between HOXD13-mediated gene activation and EWS::FLI1-dependent gene repression defines the state of Ewing sarcoma cells along a mesenchymal axis.
conclusionsEwing sarcoma tumors are comprised of tumor cells that exist along a mesenchymal transcriptional continuum. The identity of cells along this continuum is, in large part, determined by the competing activities of EWS::FLI1 and HOXD13. See related commentary by Weiss and Bailey, p. 4360.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.