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Updated: Jun 14, 2025

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell

Gaylor Boulay1,2, Liliane C Broye3, Rui Dong1

  • 1Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Nature Communications
|August 28, 2024
PubMed

Insights

Ewing sarcoma-Wilms tumor 1 (EWS-WT1) fusion proteins drive aggressive Desmoplastic Small Round Cell Tumors (DSRCT). Targeting CCND1 with Palbociclib significantly reduced tumor burden in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Desmoplastic Small Round Cell Tumor (DSRCT) is an aggressive malignancy driven by EWS-WT1 fusion proteins.
  • Understanding the gene regulatory networks controlled by EWS-WT1 is crucial for developing targeted therapies.

Purpose of the Study:

  • To identify EWS-WT1-dependent gene regulation networks and target genes in DSRCT.
  • To elucidate the distinct roles of EWS-WT1 isoforms in tumor development.
  • To discover potential therapeutic vulnerabilities in DSRCT.

Main Methods:

  • Chromatin occupancy profiling
  • 3D genome structure analysis
  • Analysis of EWS-WT1 isoforms
  • Preclinical DSRCT models (PDXs)

Main Results:

  • EWS-WT1 acts as a potent chromatin activator, orchestrating an oncogenic gene expression program in DSRCT.
  • Two distinct EWS-WT1 isoforms, differing in DNA binding domains, are both essential for DSRCT development.
  • Candidate target genes, including CCND1, were identified, showing therapeutic potential.
  • Inhibition of CCND1 by Palbociclib markedly reduced tumor burden in DSRCT patient-derived xenografts.

Conclusions:

  • This study elucidates the gene regulatory mechanisms and therapeutic vulnerabilities in DSRCT.
  • EWS-WT1's complex oncogenic activity is mechanistically understood.
  • Targeting CCND1 represents a promising therapeutic strategy for DSRCT.

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