Epigenomic Reprogramming toward Mesenchymal-Epithelial Transition in Ovarian-Cancer-Associated Mesenchymal Stem Cells Drives Metastasis.
Epigenomic Reprogramming toward Mesenchymal-Epithelial Transition in Ovarian-Cancer-Associated Mesenchymal Stem Cells Drives Metastasis.
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卵巢癌相关的间充质干细胞中的表观基因组重编程朝着间质上皮上皮转变驱动转移。
DOI：
10.1016/j.celrep.2020.108473
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发表时间：
2020-12-08
期刊：
影响因子：
8.8
通讯作者：
Coffman LG
中科院分区：
文献类型：
--
作者：
Fan H;Atiya HI;Wang Y;Pisanic TR;Wang TH;Shih IM;Foy KK;Frisbie L;Buckanovich RJ;Chomiak AA;Tiedemann RL;Rothbart SB;Chandler C;Shen H;Coffman LG
癌细胞上皮向间充质转化（EMT）在癌症中的作用已被充分确立。在这里，我们表明，除了癌细胞EMT，卵巢癌细胞转移依赖于宿主间充质干细胞（MSC）中的表观基因组间充质-上皮转化（MET）。这些重编程的MSC，称为癌相关MSC（CA-MSC），获得促肿瘤发生功能并直接结合癌细胞以充当转移驱动/伴侣。癌细胞诱导这种表观基因组MET，其特征在于增强子富集的DNA超甲基化、改变的染色质可及性和差异组蛋白修饰。这种现象似乎与临床相关，因为CA-MSC MET与患者生存率高度相关。从机制上讲，反映了发育中观察到的MET，CA-MSC中的MET由WT 1和EZH 2介导。重要的是，临床上可用的EZH 2抑制剂在卵巢癌小鼠模型中显著抑制CA-MSC介导的转移。Fan等人证明卵巢癌重编程基质细胞的表观基因组，诱导间充质-上皮转化（MET）以形成癌相关间充质干细胞（CA-MSC）。这种由WT 1和EZH 2介导的MET使CA-MSC：癌细胞共转移成为可能。EZH 2抑制减少CA-MSC介导的转移，为卵巢癌提供了潜在的治疗机会。
A role for cancer cell epithelial-to-mesenchymal transition (EMT) in cancer is well established. Here, we show that, in addition to cancer cell EMT, ovarian cancer cell metastasis relies on an epigenomic mesenchymal-to-epithelial transition (MET) in host mesenchymal stem cells (MSCs). These reprogrammed MSCs, termed carcinoma-associated MSCs (CA-MSCs), acquire pro-tumorigenic functions and directly bind cancer cells to serve as a metastatic driver/chaperone. Cancer cells induce this epigenomic MET characterized by enhancer-enriched DNA hypermethylation, altered chromatin accessibility, and differential histone modifications. This phenomenon appears clinically relevant, as CA-MSC MET is highly correlated with patient survival. Mechanistically, mirroring MET observed in development, MET in CA-MSCs is mediated by WT1 and EZH2. Importantly, EZH2 inhibitors, which are clinically available, significantly inhibited CA-MSC-mediated metastasis in mouse models of ovarian cancer. Fan et al. demonstrate that ovarian cancer reprograms the epigenome of stromal cells, inducing a mesenchymal-to-epithelial transition (MET) to form carcinoma-associated mesenchymal stem cells (CA-MSCs). This MET, mediated by WT1 and EZH2, enables CA-MSC:cancer cell co-metastasis. EZH2 inhibition decreases CA-MSC-mediated metastasis, presenting a potential therapeutic opportunity in ovarian cancer.
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