O'Donnell Edmond, Muñoz Maria, Davis Ryan, Bergonio Jessica, Randall R Lor, Tepper Clifford, Carr-Ascher Janai
Department of Orthopedic Surgery, University of California Davis, Sacramento, CA, 95817, USA.
Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, Sacramento, CA, 95817, USA.
NPJ Precis Oncol. 2025 Jan 9;9(1):7. doi: 10.1038/s41698-024-00776-7.
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. 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.
高级别软组织肉瘤（STS）是一组异质性且侵袭性强的癌症。对蒽环类化疗（标准一线治疗）无反应与不良预后相关。我们研究了STS癌症干细胞（STS-CSCs）对多柔比星耐药性的影响。我们发现CSC丰度与多柔比星IC之间存在正相关。利用来自五种肉瘤亚型的患者来源样本，我们研究了是否可以靶向STS-CSCs的共同基因特征。我们确定了增强子结合蛋白2（EZH2），它是负责H3K27甲基化的多梳抑制复合物2（PRC2）的成员，在CSCs中富集。在各亚型中均观察到EZH2活性和共同的表观遗传特征，靶向EZH2可消除STS-CSC群体。用他泽司他治疗多柔比星耐药细胞系可导致STS-CSC群体减少。这些数据证实了不同亚型的CSC-STS中存在可进行治疗靶向的共同基因程序。
