Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy.
Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome 00185, Italy.
Biosci Rep. 2024 Dec 17;44(12). doi: 10.1042/BSR20241320.
The high-grade serous ovarian cancer (HG-SOC) is a notoriously challenging disease, characterized by a rapid peritoneal dissemination. HG-SOC cells leverage actin-rich membrane protrusions, known as invadopodia, to degrade the surrounding extracellular matrix (ECM) and invade, initiating the metastatic cascade. In HG-SOC, the endothelin-1 (ET-1)/endothelin A receptor (ETAR)-driven signaling coordinates invadopodia activity, however how this axis integrates pro-oncogenic signaling routes, as YAP-driven one, impacting on the invadopodia-mediated ECM degradation and metastatic progression, deserves a deeper investigation. Herein, we observed that downstream of the ET-1/ET-1R axis, the RhoC and Rac1 GTPases, acting as signaling intermediaries, promote the de-phosphorylation and nuclear accumulation of YAP. Conversely, the treatment with the dual ETA/ETB receptor antagonist, macitentan, inhibits the ET-1-driven YAP activity. Similarly, RhoC silencing, or cell transfection with a dominant inactive form of Rac1, restores YAP phosphorylation. Mechanistically, the ET-1R/YAP signal alliance coordinates invadopodia maturation into ECM-degrading structures, indicating how such ET-1R-guided protein network represents a route able to enhance the HG-SOC invasive potential. At functional level, we found that the interconnection between the ET-1R/RhoC and YAP signals is required for MMP-2 and MMP-9 proteolytic functions, cell invasion, and cytoskeleton architecture changes, supporting the HG-SOC metastatic strength. In HG-SOC patient-derived xenografts (PDX) macitentan, turning-off the invadopodia regulators RhoC/YAP, halts the metastatic colonization. ET-1R targeting, hindering the YAP activity, weakens the invadopodia machinery, embodying a promising therapeutic avenue to prevent peritoneal dissemination in HG-SOC.
高级别浆液性卵巢癌（HG-SOC）是一种众所周知的具有挑战性的疾病，其特征是快速腹膜扩散。HG-SOC 细胞利用富含肌动蛋白的膜突起，即侵袭伪足，来降解周围的细胞外基质（ECM）并侵袭，启动转移级联。在 HG-SOC 中，内皮素-1（ET-1）/内皮素 A 受体（ETAR）驱动的信号协调侵袭伪足活性，然而，该轴如何整合致癌信号途径，如 YAP 驱动的途径，影响侵袭伪足介导的 ECM 降解和转移进展，值得更深入的研究。在此，我们观察到 ET-1/ET-1R 轴的下游，RhoC 和 Rac1 GTPases 作为信号中介物，促进 YAP 的去磷酸化和核积累。相反，用双重 ETA/ETB 受体拮抗剂马西替坦治疗可抑制 ET-1 驱动的 YAP 活性。同样，RhoC 沉默或细胞转染 Rac1 的显性失活形式可恢复 YAP 的磷酸化。从机制上讲，ET-1R/YAP 信号联盟协调侵袭伪足向 ECM 降解结构的成熟，表明这种 ET-1R 指导的蛋白质网络如何代表增强 HG-SOC 侵袭潜力的途径。在功能水平上，我们发现 ET-1R/RhoC 和 YAP 信号之间的相互联系对于 MMP-2 和 MMP-9 的蛋白水解功能、细胞侵袭和细胞骨架结构变化是必需的，支持 HG-SOC 的转移强度。在 HG-SOC 患者来源的异种移植（PDX）中，马西替坦关闭侵袭伪足调节剂 RhoC/YAP，阻止转移定植。靶向 ET-1R，抑制 YAP 活性，削弱侵袭伪足机制，为预防 HG-SOC 的腹膜扩散提供了一种有前途的治疗途径。
