Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome 00128, Italy.
Confocal Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, Rome 00161, Italy.
Cell Rep. 2021 Mar 2;34(9):108800. doi: 10.1016/j.celrep.2021.108800.
Cancer cells use actin-based membrane protrusions, invadopodia, to degrade stroma and invade. In serous ovarian cancer (SOC), the endothelin A receptor (ETR) drives invadopodia by a not fully explored coordinated function of β-arrestin1 (β-arr1). Here, we report that β-arr1 links the integrin-linked kinase (ILK)/βPIX complex to activate Rac3 GTPase, acting as a central node in the adhesion-based extracellular matrix (ECM) sensing and degradation. Downstream, Rac3 phosphorylates PAK1 and cofilin and promotes invadopodium-dependent ECM proteolysis and invasion. Furthermore, ETR/ILK/Rac3 signaling supports the communication between cancer and mesothelial cells, favoring SOC cell adhesion and transmigration. In vivo, ambrisentan, an ETR antagonist, inhibits the adhesion and spreading of tumor cells to intraperitoneal organs, and invadopodium marker expression. As prognostic factors, high EDNRA/ILK expression correlates with poor SOC clinical outcome. These findings provide a framework for the ET-1R/β-arr1 pathway as an integrator of ILK/Rac3-dependent adhesive and proteolytic signaling to invadopodia, favoring cancer/stroma interactions and metastatic behavior.
癌细胞利用基于肌动蛋白的膜突，即侵袭伪足，来降解基质并入侵。在浆液性卵巢癌（SOC）中，内皮素 A 受体（ETR）通过β-arrestin1（β-arr1）的协调功能驱动侵袭伪足，但这种功能尚未被充分探索。在这里，我们报告β-arr1 将整合素连接激酶（ILK）/βPIX 复合物与激活 Rac3 GTPase 联系起来，充当基于黏附的细胞外基质（ECM）感应和降解的中央节点。下游，Rac3 磷酸化 PAK1 和丝切蛋白，并促进侵袭伪足依赖性 ECM 蛋白水解和侵袭。此外，ETR/ILK/Rac3 信号支持癌症和间皮细胞之间的通讯，有利于 SOC 细胞的黏附和迁移。在体内，内皮素受体拮抗剂安贝生坦抑制肿瘤细胞对腹膜内器官的黏附和铺展，以及侵袭伪足标志物的表达。作为预后因素，高表达 EDNRA/ILK 与 SOC 患者的不良临床结局相关。这些发现为 ET-1R/β-arr1 途径作为整合素连接激酶（ILK）/Rac3 依赖性黏附和蛋白水解信号向侵袭伪足的整合提供了一个框架，有利于癌症/基质相互作用和转移行为。
