Schematic model illustrating the cross-talk between the ET-1R axis and the YAP pathway. The ET-1R/β-arr1-generated signaling network instructs highly specific transcriptional programs through the binding of specific transcription factors (TF) as TEAD, NFY, and HIF-1α, that impact on the behaviour of cancer cells, promoting the amplification of an ET-1 autocrine vicious circuit, critically involved in tumor cell proliferation, survival, cell invasion and migration, epithelial-to-mesenchymal transition (EMT) and chemoresistance. The autocrine/paracrine release of ET-1 may in parallel impact on tumor microenvironment (TME) elements embedded in the extracellular matrix (ECM), affecting their features. ET-1 activating the ETBR expressed by endothelial cells (EC) and lymphatic endothelial cells (LEC) promotes angiogenesis and lymphangiogenesis. Moreover, ET-1R/YAP may sustain the growth, migration and contraction of cancer-associated fibroblasts (CAF), and may favour the maturation and activity of tumor-associated macrophages (TAM), sustaining the production of inflammatory cytokines crucial for tumor metastatization. In addition, ET-1 via ETBR may interfere with the recruitment of the tumor-infiltrating lymphocytes (TIL) to the tumor. Moreover, ET-1 sustains the production of proteins that modify the architecture of the ECM. These knowledge render the ET-1R receptors suitable targets for therapeutic interventions based on the use of dual ET-1R antagonists, as macitentan, able to simultaneously interfere with the ET-1R/β-arr1-induced signaling network and YAP in tumor cells and TME elements.
Part of the figure is drawn using pictures from Servier Medical Art (https://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0)