ABSTRACT: High-grade serous ovarian cancer (HG-SOC), characterized by very frequent mutations in TP53 gene, is a highly lethal cancer and is refractory to therapeutic strategies. In HG-SOC, the reciprocal signal exchange between tumor cells and various types of stromal elements from the tumor microenvironment (TME) shapes the malignant phenotype and limits drug efficacy, suggesting that blunting the HG-SOC/TME interplay may improve the anti-tumor therapy response rate. Here, we unveil how the endothelin-1 (ET-1)/ET-1 receptors (ET-1R) signaling, instructing the mutual inter-regulation between HG-SOC cells, endothelial cells (EC) and activated fibroblasts, regulates malignant progression and PARP inhibitor (PARPi) response. Mechanistically, ET-1 axis, mimicking hypoxia, enhances the mutant p53 (mutp53)/YAP/hypoxia inducible factor-1α (HIF-1α) transcriptional cooperation, that culminates with the release of diffusible mediators, as ET-1 and VEGF, that charting a bilateral HG-SOC/stroma signaling route, regulate the acquisition of pro-metastatic traits and PARPi response. Concurrently, our study establishes that ET-1 signaling its instrumental for the activation of p53/YAP/HIF-1α transcriptional machinery within the EC and the activated fibroblasts, shaping their behaviour and secretome. The dual ET-1R antagonist macitentan, dismantling the ET-1R-mediated mutp53/YAP/HIF-1α network, interferes with the ET-1-guided tumor/stroma communication. In vivo macitentan, sensitizing HG-SOC patient-derived xenografts (PDX) to the PARPi, Olaparib, reduces their metastatic potential. Clinically relevant, ETAR/YAP/HIF-1α gene signature correlates with a dismal prognosis in HG-SOC patients. Our findings recognize in the networking between ET-1R and YAP/mutp53/HIF-1α a tumor/TME shared escaping strategy from DNA damaging agents and support the use of ET-1R antagonists in combinatorial treatments with PARPi for HG-SOC patients.
