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Key Points Aberrant expression of endothelin 1 (ET1), or overexpression of endothelin receptors or their linked signalling circuits can contribute to tumour initiation and progression through both autocrine and paracrine mechanisms. These alteration mechanisms may arise from genetic and epigenetic changes. An intricate network of crosstalk between ET1 signalling and other growth factor pathways drives tumour progression. This includes crosstalk between the endothelin receptors and epidermal growth factor receptor and vascular endothelial growth factor receptor. ET1 signalling promotes cell proliferation, survival, epithelial-to-mesenchymal transition, neovascularization, response of immune cells and drug resistance in a context-dependent manner. Hence, endothelin receptors have emerged as key targets for cancer therapy. In addition to tumour cells, endothelin receptors are found on tumour-associated host cells, such as blood and lymphatic endothelial cells, fibroblasts and inflammatory cells, thus regulating the contribution of these cell types to cancer progression. Therefore, endothelin receptor antagonists may inhibit tumour progression by blocking crucial signalling events in both the tumour microenvironment and the tumour cells. The activation of ET1 signalling pathways is often negatively correlated with patient outcomes in different types of cancer. Small-molecule antagonists for targeting endothelin receptors have been evaluated in several recent clinical trials. However, the clinical results to date have been disappointing and it is crucial to decipher why the promising preclinical data have not yet been translated to the clinic. Future improved clinical trials might incorporate predictive biomarkers to focus on subsets of patients who are most likely to respond, use other clinical settings or use rational combination therapy with chemotherapeutics or targeted agents. Endothelin 1 (ET1) is a secreted protein that can function through autocrine and paracrine signalling to modulate various properties of cancer cells and their microenvironment. This Review describes our latest understanding of the biological roles of ET1 in cancer and the results of clinical trials with drugs that target the ET1 signalling pathway. Activation of autocrine and paracrine signalling by endothelin 1 (ET1) binding to its receptors elicits pleiotropic effects on tumour cells and on the host microenvironment. This activation modulates cell proliferation, apoptosis, migration, epithelial-to-mesenchymal transition, chemoresistance and neovascularization, thus providing a strong rationale for targeting ET1 receptors in cancer. In this Review, we discuss the advances in our understanding of the diverse biological roles of ET1 in cancer and describe the latest preclinical and clinical progress that has been made using small-molecule antagonists of ET1 receptors that inhibit ET1-driven signalling.

Tumor cells acquire invasive and metastatic behavior by sensing changes in the localization and activation of signaling pathways, which in turn determine changes in actin cytoskeleton. The core-scaffold machinery associated to β-arrestin (β-arr) is a key mechanism of G-protein coupled receptors (GPCR) to achieve spatiotemporal specificity of different signaling complexes driving cancer progression. Within different cellular contexts, the scaffold proteins β-arr1 or β-arr2 may now be considered organizers of protein interaction networks involved in tumor development and metastatic dissemination. Studies have uncovered the importance of the β-arr engagement with a growing number of receptors, signaling molecules, cytoskeleton regulators, epigenetic modifiers, and transcription factors in GPCR-driven tumor promoting pathways. In many of these molecular complexes, β-arrs might provide a physical link to active dynamic cytoskeleton, permitting cancer cells to adapt and modify the tumor microenvironment to promote the metastatic spread. Given the complexity and the multidirectional β-arr-driven signaling in cancer cells, therapeutic targeting of specific GPCR/β-arr molecular mechanisms is an important avenue to explore when considering future new therapeutic options. The focus of this review is to integrate the most recent developments and exciting findings of how highly connected components of β-arr-guided molecular connections to other pathways allow precise control over multiple signaling pathways in tumor progression, revealing ways of therapeutically targeting the convergent signals in patients.

The extracellular matrix (ECM) provides critical biochemical and biophysical cues that regulate cell behavior in health and disease. Collagens dominate in abundance and structural importance, shaping tissue-specific ECM signatures that guide cellular behavior. Two major and distinct transmembrane receptor families, integrins and discoidin domain receptors (DDRs), serve as primary sensors for collagens, yet they employ fundamentally distinct binding mechanisms and signaling kinetics. While both can activate shared downstream pathways, their functional interplay remains complex and context-dependent, with the potential to fine-tune cellular responses to ECM cues. This review deciphers the nuanced crosstalk between integrin β1 and DDRs, with a particular focus on the understudied DDR2, across physiological and pathological processes. We discuss how this interplay, which evolves from cooperative to compensatory or even antagonistic signaling, is influenced by variables,  such as tissue specificity, developmental timing, and pathological context, dictating cell adhesion, migration, and ECM remodeling. Key examples include DDRs acting as allosteric regulators to license integrin activation, their partnership in mechanotransduction during development, and their divergent roles in aging tissues, where altered collagen mechanics shift the receptor hierarchy. In pathology, the DDR-integrin axis is pivotal in fibrosis and cancer, influencing fibroblast activation, drug resistance, metastatic outgrowth, and immune suppression within the tumor microenvironment. Notably, the receptors can function both independently and synergistically; for instance, DDR2 in cancer-associated fibroblasts regulates integrin-mediated mechanosignaling to promote metastasis, while in other contexts, both receptors activate distinct survival pathways. Understanding the signaling dynamics and mechanisms of these receptors is necessary for deciphering how cells interpret ECM signals and how these mechanisms contribute to disease progression, especially in those diseases marked by collagen remodeling. This comprehension is crucial for developing novel therapeutic strategies. Emerging evidence suggests that combined targeting DDRs and integrins can synergistically overcome ECM-mediated therapy resistance, enhance immune infiltration, and reprogram pathological microenvironments, offering a promising approach for treating fibrosis and collagen-rich cancers.

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, ET A R/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. YAP and mutant p53 crosstalk to regulate transcriptional processes in cancers. Here, the authors show that endothelin-1 mediated activation of β-arrestin interacts with YAP to recruit mutant p53 to the TEAD/YAP complex to promote metastasis and chemoresistance in ovarian cancer.

During the metastatic progression, invading cells might achieve degradation and subsequent invasion into the extracellular matrix (ECM) and the underlying vasculature using invadopodia, F-actin-based and force-supporting protrusive membrane structures, operating focalized proteolysis. Their formation is a dynamic process requiring the combined and synergistic activity of ECM-modifying proteins with cellular receptors, and the interplay with factors from the tumor microenvironment (TME). Significant advances have been made in understanding how invadopodia are assembled and how they progress in degradative protrusions, as well as their disassembly, and the cooperation between cellular signals and ECM conditions governing invadopodia formation and activity, holding promise to translation into the identification of molecular targets for therapeutic interventions. These findings have revealed the existence of biochemical and mechanical interactions not only between the actin cores of invadopodia and specific intracellular structures, including the cell nucleus, the microtubular network, and vesicular trafficking players, but also with elements of the TME, such as stromal cells, ECM components, mechanical forces, and metabolic conditions. These interactions reflect the complexity and intricate regulation of invadopodia and suggest that many aspects of their formation and function remain to be determined. In this review, we will provide a brief description of invadopodia and tackle the most recent findings on their regulation by cellular signaling as well as by inputs from the TME. The identification and interplay between these inputs will offer a deeper mechanistic understanding of cell invasion during the metastatic process and will help the development of more effective therapeutic strategies.

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.

Background Peritoneal metastasis, which accounts for 85% of all epithelial ovarian carcinoma (EOC) metastases, is a multistep process that requires the establishment of adhesive interactions between cancer cells and the peritoneal membrane. Interrelations between EOC and the mesothelial stroma are critical to facilitate the metastatic process. No data is available so far on the impact of histone acetylation/deacetylation, a potentially relevant mechanism governing EOC metastasis, on mesothelial cells (MCs)-mediated adhesion. Methods Static adhesion and peritoneal clearance experiments were performed pretreating mesenchymal-like MCs and platinum—sensitive/resistant EOC cell lines with MS-275—a Histone deacetylase (HDAC)1–3 pharmacological inhibitor currently used in combination trials. Results were acquired by confocal microscopy and were analyzed with an automated Opera software. The role of HDAC1/2 was validated by genetic silencing. The role of α4-, α5-α1 Integrins and Fibronectin-1 was validated using specific monoclonal antibodies. Quantitative proteomic analysis was performed on primary MCs pretreated with MS-275. Decellularized matrices were generated from either MS-275-exposed or untreated cells to study Fibronectin-1 extracellular secretion. The effect of MS-275 on β1 integrin activity was assessed using specific monoclonal antibodies. The role of Talin-1 in MCs/EOC adhesion was analyzed by genetic silencing. Talin-1 ectopic expression was validated as a rescue tool from MS-275-induced phenotype. The in vivo effect of MS-275-induced MC remodeling was validated in a mouse model of peritoneal EOC dissemination. Results Treatment of MCs with non-cytotoxic concentrations of MS-275 caused a consistent reduction of EOC adhesion. Proteomic analysis revealed several pathways altered upon MC treatment with MS-275, including ECM deposition/remodeling, adhesion receptors and actin cytoskeleton regulators. HDAC1/2 inhibition hampered actin cytoskeleton polymerization by downregulating actin regulators including Talin-1, impairing β1 integrin activation, and leading to abnormal extracellular secretion and distribution of Fibronectin-1. Talin-1 ectopic expression rescued EOC adhesion to MS-275-treated MCs. In an experimental mouse model of metastatic EOC, MS-275 limited tumor invasion, Fibronectin-1 secretion and the sub-mesothelial accumulation of MC-derived carcinoma-associated fibroblasts. Conclusion Our study unveils a direct impact of HDAC-1/2 in the regulation of MC/EOC adhesion and highlights the regulation of MC plasticity by epigenetic inhibition as a potential target for therapeutic intervention in EOC peritoneal metastasis.

The advent of targeted therapeutics in human cancer has begun to find novel druggable targets and, in this context, the endothelin-1 receptor (ET-1R), namely ET A receptor (ET A R) and ET B receptor, among the GPCR family represents a class of highly druggable molecules in cancer. ET-1R are aberrantly expressed in human malignancies, potentially representing prognostic factors. Their activation by ligand stimulation initiate signaling cascades activating different downstream effectors, allowing precise control over multiple signaling pathways. ET-1R regulates cell proliferation, survival, motility, cytoskeletal changes, angiogenesis, metastasis as well as drug resistance. The molecular events underlying these responses are the activation of transcriptional factors and coactivators, and downstream genes, acting as key players in tumor growth and progression. ET-1R represent crucial cancer targets that have been exploited for ET-1R therapeutics. Importantly, efforts to explore new information of ET A R in cancer have uncovered that their functions are crucially regulated by multifunctional scaffold protein β-arrestins (β-arrs) which orchestrate the multidimensionality of ET A R signaling into highly regulated and distinct signaling complexes, a property that is highly advantageous for tumor signaling. Moreover, the role of β-arr1 in ET-1 signaling in cancer highlights why the pleiotropic effects of ET-1 and its dynamic signaling are more complex than previously recognized. In order to improve therapeutic strategies that interfere with the widespread effects of ET-1R, it is important to consider antagonists able to turn the receptors “off” selectively controlling β-arr1-dependent signaling, highlighting the possibility that targeting ET A R/β-arr1 may display a large therapeutic window in cancer.

Recruitment of fibroblasts to tumors and their activation into cancer-associated fibroblasts (CAFs) is a strategy used by tumor cells to direct extracellular matrix (ECM) remodeling, invasion, and metastasis, highlighting the need to investigate the molecular mechanisms driving CAF function. Endothelin-1 (ET-1) regulates the communication between cancer and stroma and facilitates the progression of serous ovarian cancer (SOC). By binding to Endothelin A (ET A ) and B (ET B ) receptors, ET-1 enables the recruitment of β-arrestin1 (β-arr1) and the formation of signaling complexes that coordinate tumor progression. However, how ET-1 receptors might “educate” human ovarian fibroblasts (HOFs) to produce altered ECM and promote metastasis remains to be elucidated. This study identifies ET-1 as a pivotal factor in the activation of CAFs capable of proteolytic ECM remodeling and the generation of heterotypic spheroids containing cancer cells with a propensity to metastasize. An autocrine/paracrine ET-1/ET A/B R/β-arr1 loop enhances HOF proliferation, upregulates CAF marker expression, secretes pro-inflammatory cytokines, and increases collagen contractility, and cell motility. Furthermore, ET-1 facilitates ECM remodeling by promoting the lytic activity of invadosome and activation of integrin β1. In addition, ET-1 signaling supports the formation of heterotypic HOF/SOC spheroids with enhanced ability to migrate through the mesothelial monolayer, and invade, representing metastatic units. The blockade of ET A/B R or β-arr1 silencing prevents CAF activation, invadosome function, mesothelial clearance, and the invasive ability of heterotypic spheroids. In vivo, therapeutic inhibition of ET A/B R using bosentan (BOS) significantly reduces the metastatic potential of combined HOFs/SOC cells, associated with enhanced apoptotic effects on tumor cells and stromal components. These findings support a model in which ET-1/β-arr1 reinforces tumor/stroma interaction through CAF activation and fosters the survival and metastatic properties of SOC cells, which could be counteracted by ET A/B R antagonists.

The limited clinical response to conventional chemotherapeutics observed in colorectal cancer (CRC) may be related to the connections between the hyperactivated β -catenin signaling and other pathways in CRC stem-like cells (CRC-SC). Here, we show the mechanistic link between the endothelin-1 (ET-1)/ET-1 receptor (ET-1R) signaling and β -catenin pathway through the specific interaction with the signal transducer β -arrestin1 ( β -arr1), which initiates signaling cascades as part of the signaling complex. Using a panel of patient-derived CRC-SC, we show that these cells secrete ET-1 and express ET A R and β -arr1, and that the activation of ET A R/ β -arr1 axis promotes the cross-talk with β -catenin signaling to sustain stemness, epithelial-to-mesenchymal transition (EMT) phenotype and response to chemotherapy. Upon ET A R activation, β -arr1 acts as a transcription co-activator that binds β -catenin, thereby promoting nuclear complex with β -catenin/TFC4 and p300 and histone acetylation, inducing chromatin reorganization on target genes, such as ET-1. The enhanced transcription of ET-1 increases the self-sustained ET-1/ β -catenin network. All these findings provide a strong rationale for targeting ET-1R to hamper downstream β -catenin/ET-1 autocrine circuit. Interestingly, treatment with macitentan, a dual ET A R and ET B R antagonist, able to interfere with tumor and microenvironment, disrupts the ET-1R/ β -arr1- β -catenin interaction impairing pathways involved in cell survival, EMT, invasion, and enhancing sensitivity to oxaliplatin (OX) and 5-fluorouracil (5-FU). In CRC-SC xenografts, the combination of macitentan and OX or 5-FU enhances the therapeutic effects of cytotoxic drugs. Together, these results provide mechanistic insight into how ET-1R coopts β -catenin signaling and offer a novel therapeutic strategy to manage CRC based on the combination of macitentan and chemotherapy that might benefit patients whose tumors show high ET A R and β -catenin expression.