Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium.
Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium.
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葡萄膜黑色素瘤细胞使用阿米巴样和间充质机制的细胞运动穿过内皮。
DOI：
10.1091/mbc.e20-04-0241
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发表时间：
2021-03-01
影响因子：
3.3
通讯作者：
Cooper JA
中科院分区：
文献类型：
--
作者：
Onken MD;Blumer KJ;Cooper JA
葡萄膜黑色素瘤（UMs）是从眼睛的色素层产生的恶性癌症。UM细胞通过血流扩散，并且在转移出现之前在患者中可检测到循环UM细胞。UM细胞的外渗是转移瘤形成所必需的，而跨内皮迁移（TEM）是外渗的关键步骤。UM细胞执行TEM通过一个逐步的过程，涉及肌动蛋白为基础的过程，阿米巴水泡和间充质板状伪足突起。UM癌症由激活Gαq/11的致癌突变驱动，这激活了TRIO，一种RhoA和Rac 1的鸟嘌呤核苷酸交换因子。我们发现，药物抑制UM细胞中的Gαq/11可降低TEM。抑制RhoA通路阻断了阿米巴样运动，但导致增强TEM;相反，抑制Rac 1通路降低了间充质运动并减少了TEM。Arp 2/3复合物的抑制允许细胞在没有嵌入的情况下迁移，这是一种与免疫细胞经常显示的机制类似的直接机制。BAP 1缺陷（+/-）UM亚克隆显示运动行为和增加的TEM水平，类似于RhoA抑制剂的作用。结论：RhoA和Rac 1信号通路位于致癌基因Gαq/11的下游，联合收割机与BAP 1调控的信号通路共同调控UM细胞的运动和迁移。
Uveal melanomas (UMs) are malignant cancers arising from the pigmented layers of the eye. UM cells spread through the bloodstream, and circulating UM cells are detectable in patients before metastases appear. Extravasation of UM cells is necessary for formation of metastases, and transendothelial migration (TEM) is a key step in extravasation. UM cells execute TEM via a stepwise process involving the actin-based processes of ameboid blebbing and mesenchymal lamellipodial protrusion. UM cancers are driven by oncogenic mutations that activate Gαq/11, and this activates TRIO, a guanine nucleotide exchange factor for RhoA and Rac1. We found that pharmacologic inhibition of Gαq/11 in UM cells reduced TEM. Inhibition of the RhoA pathway blocked amoeboid motility but led to enhanced TEM; in contrast, inhibition of the Rac1 pathway decreased mesenchymal motility and reduced TEM. Inhibition of Arp2/3 complex allowed cells to transmigrate without intercalation, a direct mechanism similar to the one often displayed by immune cells. BAP1-deficient (+/–) UM subclones displayed motility behavior and increased levels of TEM, similar to the effects of RhoA inhibitors. We conclude that RhoA and Rac1 signaling pathways, downstream of oncogenic Gαq/11, combine with pathways regulated by BAP1 to control the motility and transmigration of UM cells.