Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target
Abstract 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 resist...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-024-00776-7 |
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| author | Edmond O’Donnell Maria Muñoz Ryan Davis Jessica Bergonio R. Lor Randall Clifford Tepper Janai Carr-Ascher |
| author_facet | Edmond O’Donnell Maria Muñoz Ryan Davis Jessica Bergonio R. Lor Randall Clifford Tepper Janai Carr-Ascher |
| author_sort | Edmond O’Donnell |
| collection | DOAJ |
| description | Abstract 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 IC50. 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. |
| format | Article |
| id | doaj-art-f0fa6d57acfc453eae35a0e0045d73b6 |
| institution | Kabale University |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-f0fa6d57acfc453eae35a0e0045d73b62025-01-12T12:06:21ZengNature Portfolionpj Precision Oncology2397-768X2025-01-019111110.1038/s41698-024-00776-7Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic targetEdmond O’Donnell0Maria Muñoz1Ryan Davis2Jessica Bergonio3R. Lor Randall4Clifford Tepper5Janai Carr-Ascher6Department of Orthopedic Surgery, University of California DavisDepartment of Internal Medicine, Division of Hematology/Oncology, University of California DavisDepartment of Pathology and Laboratory, University of California DavisDepartment of Internal Medicine, Division of Hematology/Oncology, University of California DavisDepartment of Orthopedic Surgery, University of California DavisDepartment of Pathology and Laboratory, University of California DavisDepartment of Orthopedic Surgery, University of California DavisAbstract 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 IC50. 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.https://doi.org/10.1038/s41698-024-00776-7 |
| spellingShingle | Edmond O’Donnell Maria Muñoz Ryan Davis Jessica Bergonio R. Lor Randall Clifford Tepper Janai Carr-Ascher Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target npj Precision Oncology |
| title | Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target |
| title_full | Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target |
| title_fullStr | Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target |
| title_full_unstemmed | Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target |
| title_short | Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target |
| title_sort | genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies ezh2 as a therapeutic target |
| url | https://doi.org/10.1038/s41698-024-00776-7 |
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