Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target
High-grade soft tissue sarcomas (STS) are a heterogeneous and aggressive set of cancers. Failure to respond anthracycline chemotherapy, standard first-line treatment, is associated with poor outcomes. We investigated the contribution of STS cancer stem cells (STS-CSCs) to doxorubicin resistance. We identified a positive correlation between CSC abundance and doxorubicin IC<sub>50</sub>. Utilizing patient-derived samples from five sarcoma subtypes we investigated if a common genetic signature across STS-CSCs could be targeted. We identified Enhancer of Zeste homolog 2 (EZH2), a member of the polycomb repressive complex 2 (PRC2) responsible for H3K27 methylation as being enriched in CSCs. EZH2 activity and a shared epigenetic profile was observed across subtypes and targeting of EZH2 ablated the STS-CSC population. Treatment of doxorubicin-resistant cell lines with tazemetostat resulted in a decrease in the STS-CSC population. These data confirm the presence of shared genetic programs across distinct subtypes of CSC-STS that can be therapeutically targeted.
Authors
- Clifford G. Tepper (ORCID: https://orcid.org/0000-0001-7105-1102)
- Edmond F. O’Donnell (ORCID: https://orcid.org/0000-0001-9110-9981)
- Ryan R. Davis (ORCID: https://orcid.org/0000-0001-7439-6683)
- Janai R. Carr (ORCID: https://orcid.org/0000-0002-2074-4643)
- Maria Muñoz
- R. Lor Randall (ORCID: https://orcid.org/0000-0002-3660-774X)
- Jessica Bergonio
Institutions
- University of California, Davis (US)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-01-09
- DOI
- https://doi.org/10.1038/s41698-024-00776-7
- Citations
- 5
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- National Institutes of Health
- University of California, Davis
- National Cancer Institute
- Comprehensive Cancer Center, University of California, Davis