Targeting tumor-stroma communication by blocking endothelin-1 receptor signaling sensitizes high-grade serous ovarian cancer to PARP inhibitor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA803193 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17873520.fastq.gz | Fastqsanger.gz | |||
| SRR17873521.fastq.gz | Fastqsanger.gz | |||
| SRR17873522.fastq.gz | Fastqsanger.gz | |||
| SRR17873523.fastq.gz | Fastqsanger.gz | |||
| SRR17873524.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:PARP inhibitors (PARPi) have changed the treatment paradigm of high-grade serous ovarian cancer (HG-SOC). However, the impact of this class of inhibitors in HG-SOC patients with a high rate of TP53 mutations is limited, highlighting the need to develop combinatorial therapeutic strategies to improve responses to PARPi. Here, we unveil how the endothelin-1/ET-1 receptor (ET-1/ET-1R) axis, which is overexpressed in human HG-SOC and associated with poor prognosis, instructs HG-SOC/tumor microenvironment (TME) communication via key pro-malignant factors and restricts the DNA damage response induced by the PARPi olaparib. Mechanistically, the ET-1 axis promotes the p53/YAP/hypoxia inducible factor-1α (HIF-1α) transcription hub connecting HG-SOC cells, endothelial cells and activated fibroblasts, hence fueling persistent DNA damage signal escape. The ET-1R antagonist macitentan, which dismantles the ET-1R-mediated p53/YAP/HIF-1α network, interferes with HG-SOC/stroma interactions that blunt PARPi efficacy. Pharmacological ET-1R inhibition by macitentan in orthotopic HG-SOC patient-derived xenografts synergizes with olaparib to suppress metastatic progression, enhancing PARPi survival benefit. These findings reveal ET-1R as a mechanistic determinant in the regulation of HG-SOC/TME crosstalk and DNA damage response, indicating the use of macitentan in combinatorial treatments with PARPi as a promising and emerging therapy.
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Project description: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 ETAR and β-arr1, and that the activation of ETAR/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 ETAR 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 ETAR and ETBR 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 ETAR and β-catenin expression.
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