Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
J Cell Biol. 2023 Nov 6;222(11). doi: 10.1083/jcb.202209114. Epub 2023 Sep 22.
The transmembrane serine protease matriptase is a key regulator of both barrier-disruptive and protective epithelial cell-cell interactions. Elevated matriptase is a consistent feature of epithelial ovarian cancers (OvCa), where multicellular spheroids shed from the primary tumor into the peritoneal cavity are critical drivers of metastasis. Dynamic cell-to-cell adhesive contacts are required for spheroid formation and maintenance. Here, we show that overactive matriptase, reflected in an increased ratio of matriptase to its inhibitor hepatocyte growth factor activator inhibitor 1 (HAI-1), disrupts cell-cell contacts to produce loose prometastatic spheroids that display increased mesothelial cell adhesion and submesothelial invasion. We show that these activities are dependent on the matriptase activation of a protease-activated receptor-2 (PAR-2) signaling pathway involving PI3K/Akt and MMP9-induced disruption of cell-cell adhesion by the release of the soluble E-cadherin ectodomain. These data reveal a novel pathological connection between matriptase activation of PAR-2 and disruption of cell-cell adhesion, and support the clinical investigation of this signaling axis as a therapeutic strategy for aggressive metastatic OvCa.
跨膜丝氨酸蛋白酶 matriptase 是调节破坏和保护上皮细胞-细胞相互作用的关键调节因子。上皮性卵巢癌（OvCa）中存在升高的 matriptase，这是肿瘤多细胞球体从原发性肿瘤脱落到腹腔中并成为转移关键驱动力的一致特征。球体的形成和维持需要动态的细胞-细胞黏附接触。在这里，我们表明，过度活跃的 matriptase，表现为 matriptase 与其抑制剂肝细胞生长因子激活物抑制剂 1（HAI-1）的比值增加，破坏细胞-细胞接触，产生疏松的促转移球体，这些球体表现出增加的间皮细胞黏附和亚间皮下浸润。我们表明，这些活性依赖于 matriptase 对蛋白酶激活受体-2（PAR-2）信号通路的激活，该通路涉及 PI3K/Akt 和 MMP9 诱导的细胞-细胞黏附的破坏，通过释放可溶性 E-钙黏蛋白外显子。这些数据揭示了 matriptase 激活 PAR-2 与细胞-细胞黏附破坏之间的新的病理联系，并支持将该信号轴作为侵袭性转移性 OvCa 的治疗策略进行临床研究。
