Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, 00144, Rome, Italy.
Oncogenomic and Epigenetic Unit, IRCCS, Regina Elena National Cancer Institute, 00144, Rome, Italy.
Nat Commun. 2019 Jul 19;10(1):3196. doi: 10.1038/s41467-019-11045-8.
The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that β-arrestin1 (β-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows β-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, β-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through β-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the β-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ETR/β-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC. These findings support effective combinatorial treatment for repurposing the ET-1R antagonists in HG-SOC.
在高频 TP53 突变（mutp53）的高级别浆液性卵巢癌（HG-SOC）中观察到的有限临床反应可能与 mutp53 驱动的致癌途径网络有关。在这里，我们表明β-arrestin1（β-arr1）与 YAP 相互作用，触发其细胞质-核穿梭。这种相互作用允许β-arr1 在患者来源的 HG-SOC 细胞和携带 mutp53 的细胞系中内皮素-1 受体（ET-1R）激活后，将 mutp53 募集到 YAP-TEAD 转录复合物中。平行地，β-arr1 介导 ET-1R 诱导的 Trio/RhoA 依赖性 YAP 核积累。在细胞核中，内皮素通过β-arr1 协调 YAP 和 mutp53 与 YAP/mutp53 靶基因启动子的连接，包括确保持续信号的 EDN1。对患者来源的异种移植物的治疗揭示了双重内皮素-1 受体拮抗剂马西替坦与顺铂联合使用的协同抗肿瘤和抗转移作用，从而阻断了β-arr1 介导的 YAP/mutp53 转录程序。此外，ETR/β-arr1/YAP 基因特征与 HG-SOC 的最差预后相关。这些发现支持对 HG-SOC 重新利用内皮素-1 受体拮抗剂进行有效的联合治疗。
