Fibrin Stiffness Mediates Dormancy of Tumor-Repopulating Cells via a Cdc42-Driven Tet2 Epigenetic Program
Fibrin Stiffness Mediates Dormancy of Tumor-Repopulating Cells via a Cdc42-Driven Tet2 Epigenetic Program
复制标题
纤维蛋白硬度通过 Cdc42 驱动的 Tet2 表观遗传程序介导肿瘤再生细胞的休眠
DOI：
10.1158/0008-5472.can-17-3719
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发表时间：
2018-07-15
期刊：
影响因子：
11.2
通讯作者：
Huang, Bo
中科院分区：
文献类型：
--
作者：
Liu, Yuying;Lv, Jiadi;Huang, Bo
休眠被认为是致瘤细胞在极其恶劣的环境中生存的关键生物学事件。了解休眠的分子过程可以开启治疗癌症的新方法。我们最近报道了干细胞样肿瘤再生细胞 (TRC) 感知机械信号并在 90 Pa 的软纤维蛋白基质中快速增殖。在这里，我们表明，僵硬的机械环境通过表观遗传程序诱导 TRC 休眠，该程序是由 Cdc42（一种机械转导的胞质调节因子）易位到细胞核中，在细胞核中促进羟甲基化酶 Tet2 的转录。 Tet2 表观遗传激活细胞周期抑制基因 p21 和 p27 以诱导休眠，但也会引起整合素 β 3 的下调以维持休眠。这种硬度介导的休眠在小鼠和原发性人类黑色素瘤 TRC 的小鼠模型中得到了重现。这些数据确定了由力学指导的表观遗传程序，该程序可驱动高致瘤性TRC在僵硬的机械环境中进入休眠状态。意义：力学指导的表观遗传程序使肿瘤再生细胞在僵硬的机械环境中进入休眠状态。 (C) 2018 年 AACR。
Dormancy is recognized as a critical biological event for tumorigenic cells surviving in an extremely harsh environment. Understanding the molecular process of dormancy can unlock novel approaches to tackle cancers. We recently reported that stem-like tumor-repopulating cells (TRC) sense mechanical signals and rapidly proliferate in a 90 Pa soft fibrin matrix. Here, we show that a stiff mechanical environment induces TRC dormancy via an epigenetic program initiated by translocation of Cdc42, a cytosolic regulator of mechanotransduction, into the nucleus, where it promotes transcription of hydroxymethylating enzyme Tet2. Tet2 epigenetically activated cell-cycle-inhibiting genes p21 and p27 to induce dormancy, but also caused downregulation of integrin beta 3 to maintain dormancy. This stiffness-mediated dormancy was recapitulated in mouse models for both murine and primary human melanoma TRCs. These data identify an epigenetic program directed by mechanics, which drives highly tumorigenic TRCs to enter dormancy in a stiff mechanical environment.Significance: A mechanics-directed epigenetic program enables tumor-repopulating cells to enter dormancy in a stiff mechanical environment. (C) 2018 AACR.