EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma.

Autor:	Apfelbaum AA; Cancer Biology PhD Program, University of Michigan, Ann Arbor, Michigan.; Seattle Children's Research Institute, Seattle, Washington., Wu F; Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington., Hawkins AG; Childhood Cancer Data Lab Alex's Lemonade Stand Foundation, Philadelphia, Pennsylvania., Magnuson B; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan., Jiménez JA; Cancer Biology PhD Program, University of Michigan, Ann Arbor, Michigan., Taylor SD; Seattle Children's Research Institute, Seattle, Washington., Wrenn ED; Seattle Children's Research Institute, Seattle, Washington., Waltner O; Fred Hutch Cancer Research Center, Seattle, Washington., Pfaltzgraff ER; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan., Song JY; Immunology Discovery, Genentech, Inc., South San Francisco, California., Hall C; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Wellik DM; Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin., Ljungman M; Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan., Furlan SN; Fred Hutch Cancer Research Center, Seattle, Washington.; Department of Pediatrics, University of Washington, Seattle, Washington., Ryan RJH; Immunology Discovery, Genentech, Inc., South San Francisco, California., Sarthy JF; Fred Hutch Cancer Research Center, Seattle, Washington.; Department of Pediatrics, University of Washington, Seattle, Washington., Lawlor ER; Seattle Children's Research Institute, Seattle, Washington.; Department of Pediatrics, University of Washington, Seattle, Washington.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Oct 14; Vol. 28 (20), pp. 4466-4478.
DOI:	10.1158/1078-0432.CCR-22-0384
Abstrakt:	Purpose: Propagation 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 Design: Existing 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. Results: We 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. Conclusions: Ewing 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. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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