Biosignal Research Center, Kobe University, Kobe, Hyogo, 657-8501, Japan.
Division of Membrane Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan.
Nat Commun. 2021 Oct 11;12(1):5930. doi: 10.1038/s41467-021-26156-4.
Malignancy is associated with changes in cell mechanics that contribute to extensive cell deformation required for metastatic dissemination. We hypothesized that the cell-intrinsic physical factors that maintain epithelial cell mechanics could function as tumor suppressors. Here we show, using optical tweezers, genetic interference, mechanical perturbations, and in vivo studies, that epithelial cells maintain higher plasma membrane (PM) tension than their metastatic counterparts and that high PM tension potently inhibits cancer cell migration and invasion by counteracting membrane curvature sensing/generating BAR family proteins. This tensional homeostasis is achieved by membrane-to-cortex attachment (MCA) regulated by ERM proteins, whose disruption spontaneously transforms epithelial cells into a mesenchymal migratory phenotype powered by BAR proteins. Consistently, the forced expression of epithelial-mesenchymal transition (EMT)-inducing transcription factors results in decreased PM tension. In metastatic cells, increasing PM tension by manipulating MCA is sufficient to suppress both mesenchymal and amoeboid 3D migration, tumor invasion, and metastasis by compromising membrane-mediated mechanosignaling by BAR proteins, thereby uncovering a previously undescribed mechanical tumor suppressor mechanism.
恶性肿瘤与细胞力学的变化有关，这些变化有助于转移扩散所需的广泛细胞变形。我们假设维持上皮细胞力学的细胞内在物理因素可以作为肿瘤抑制因子发挥作用。在这里，我们使用光学镊子、遗传干扰、力学干扰和体内研究表明，上皮细胞保持比其转移性对应物更高的质膜 (PM) 张力，并且高 PM 张力通过抵消膜曲率感应/生成 BAR 家族蛋白强力抑制癌细胞迁移和侵袭。这种紧张的动态平衡是通过 ERM 蛋白调节的质膜到皮质的附着 (MCA) 实现的，ERM 蛋白的破坏会自发地将上皮细胞转化为由 BAR 蛋白驱动的间质迁移表型。一致地，强制表达上皮-间质转化 (EMT)-诱导转录因子会导致 PM 张力降低。在转移性细胞中，通过操纵 MCA 增加 PM 张力足以通过破坏 BAR 蛋白介导的膜介导机械信号转导来抑制间质和阿米巴样 3D 迁移、肿瘤侵袭和转移，从而揭示了一种以前未描述的机械肿瘤抑制机制。
