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Publications

Journal Article Ppublish

PubMed: 40029262 DOI: 10.1158/1078-0432.CCR-24-2040

Single-Cell RNA Sequencing of Ewing Sarcoma Tumors Demonstrates Transcriptional Heterogeneity and Clonal Evolution.

Clin Cancer Res 31(10):2010-2023

Authors: Andrew Goodspeed, Avery Bodlak, Alexis B Duffy, Sarah Nelson-Taylor, Naoki Oike, Timothy Porfilio, Ryota Shirai, Deandra Walker, Amanda Treece, Jennifer Black, Nathan Donaldson, Carrye Cost, Timothy Garrington, Brian Greffe, Sandra Luna-Fineman, Jenna Demedis, Jessica Lake, Etienne Danis, Michael R Verneris, Daniel L Adams, Masanori Hayashi

Affiliations

  • University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
  • Creatv MicroTech, Monmouth Junction, New Jersey.
  • Department of Pathology and Laboratory Medicine, Children's of Alabama, Birmingham, Alabama.
  • Department of Orthopedics, University of Colorado School of Medicine, Aurora, Colorado.

Abstract

PURPOSE

Ewing sarcoma is the second most common bone cancer in children, accounting for 2% of pediatric cancer diagnoses. Patients who present with metastatic disease at the time of diagnosis have a dismal prognosis compared with the >70% 5-year survival of those with localized disease. Novel therapeutic approaches that can impact metastatic disease are desperately needed, as well as a deeper understanding of the heterogeneity of Ewing sarcoma tumors.

EXPERIMENTAL DESIGN

In this study, we utilized single-cell RNA sequencing to characterize the transcriptional landscape of primary Ewing sarcoma tumors and the surrounding tumor microenvironment in a cohort of seven untreated patients with Ewing sarcoma, as well as in circulating tumor cells (CTC). A potential CTC therapeutic target was evaluated through immunofluorescence of fixed CTCs from a separate cohort.

RESULTS

Primary tumor samples demonstrate a heterogeneous transcriptional landscape with several conserved gene expression programs, including those composed of genes related to proliferation and Ewing sarcoma gene targets, which were found to correlate with overall survival. Copy-number analysis identified subclonal evolution within patients prior to treatment. Analyses of the immune microenvironment reveal an immunosuppressive microenvironment with complex intercellular communication among the tumor and immune cells. Single-cell RNA sequencing and immunofluorescence of CTCs at the time of diagnosis identified TSPAN8 as a potential therapeutic target.

CONCLUSIONS

Ewing sarcoma tumors demonstrate significant transcriptional heterogeneity as well as a complex immunosuppressive microenvironment. This work evaluates several proposed targets that warrant further exploration as novel therapeutic strategies.

MeSH

Cells, Genes, Sarcoma, Ewing, Neoplasms, Sarcoma, Clonal Evolution, Diagnosis, Therapeutics