HMENA is a key regulator in endothelin-1/\u3b2-arrestin1- induced invadopodial function and metastatic process

Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by \u3b2-arrestin1 (\u3b2-arr1)-driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of \u3b2-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENA\u3b4v6 isoforms through \u3b2-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of \u3b2-arr1 with hMENA/hMENA\u3b4v6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of \u3b2-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ETAR/hMENA/\u3b2-arr1 gene expression signature is associated with a poor prognosis in SOC patients. These data define a pivotal function of hMENA/hMENA\u3b4v6 for ET-1/ \u3b2-arr1-induced invadopodial activity and ovarian cancer progression

In reply to Sch\ue4fer et\ua0al: new evidence on the role of endothelin-1 axis as a potential therapeutic target in multiple myeloma

no abstract availabl

\u3b2-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer

he 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 \u3b2-arrestin1 (\u3b2-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows \u3b2-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, \u3b2-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through \u3b2-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 \u3b2-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ETAR/\u3b2-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