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Targeting tumor-stroma communication by blocking endothelin-1 receptor signaling sensitizes high-grade serous ovarian cancer to PARP inhibitor

ABSTRACT: Targeting tumor-stroma communication by blocking endothelin-1 receptor signaling sensitizes high-grade serous ovarian cancer to PARP inhibitor

PROVIDER: PRJNA803193 | ENA |

REPOSITORIES: ENA

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			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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Targeting tumor-stroma communication by blocking endothelin-1 receptor signaling sensitizes high-grade serous ovarian cancer to PARP inhibitor

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.

2023-01-11 | GSE196065 | GEO

Targeting tumor-stroma communication by blocking endothelin-1 receptors sensitizes high-grade serous ovarian cancer to PARP inhibition.

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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The endothelin-1-driven tumor-stroma feed-forward loops in high-grade serous ovarian cancer

Project description:The endothelin-1-driven tumor-stroma feed-forward loops in high-grade serous ovarian cancer

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Progenitor-derived endothelin controls dermal sheath contraction for hair follicle regression

Project description:Progenitor cell death and dermal papilla relocation during the regression phase of the hair growth cycle are essential for stem cell activation and follicle regeneration. This drastic follicle remodeling is coordinated by dermal sheath (DS) smooth muscle contraction, but how DS-generated forces are regulated is unknown. Here, we identify endothelin signaling - a potent vasoconstriction-regulating pathway - as the key activating mechanism of DS contraction. Pharmacological blocking or genetic ablation of both endothelin receptors, ETA and ETB, impedes DS contraction and halts follicle regression. Progenitors at the epithelial strand bottleneck are the main source of endothelin ligand ET-1, which is required for follicle regression. ET signaling in DS cells and downstream contraction is dynamically regulated by cytoplasmic Ca2+ levels via cell membrane and sarcoplasmic reticulum calcium channels. Together, these findings illuminate an epithelial-mesenchymal-interaction paradigm in which progenitors - before undergoing programmed cell death - control the contraction of the surrounding sheath smooth muscle to orchestrate homeostatic tissue regression and follicle reorganization.

2022-10-31 | GSE215133 | GEO

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Phosphoproteomics of endothelin signalling

Project description:Time resolved phosphorylation changes were measured the melanoma cell lines A2058 and UACC257. An endothelin B receptor knockout of UACC257 was processed in parallel. Protein abundance was also compared at the latest time point of the study (90 min) using DIA-SWATH

2019-10-09 | PXD012316 | Pride

Depletion of PARP-2 in HepG2 cells

Project description:Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in liver. Microarray analysis of PARP-2 knockdown HepG2 cells revealed the dysregulation of lipid and cholesterol metabolism genes. Induction of cholesterol biosynthesis genes stemmed from the enhanced expression of sterol-regulatory element binding protein (SREBP)-1. We revealed that PARP-2 is a suppressor of the SREBP-1 promoter, therefore ablation of PARP-2 induces SREBP-1 expression and consequently cholesterol synthesis. PARP-2-/- mice had higher SREBP-1 expression that was translated into enhanced hepatic and serum cholesterol levels. PARP-2 silencing was performed employing shPARP-2 (small hairpin) and scPARP-2 (scrambled) shRNA by lentiviral delivery (Sigma) using 40 MOI lentiviruses coding shRNA sequence against PARP-2.

2013-12-31 | E-GEOD-43981 | biostudies-arrayexpress

Endothelin signaling activates neural crest gene expression via a MEF2C-dependent positive-feedback transcriptional mechanism

Project description:Endothelin signaling is one of the essential signaling pathways that control vertebrate development. Dysregulated Endothelin signaling plays an important role in the pathogenesis of human diseases such as Hirschsprung’s disease, pulmonary hypertension and cancer. However, the downstream transcriptional program and transcriptional factors of Endothelin signaling have been incompletely understood. Here, we used RNA-sequencing to identify the genes regulated by Endothelin signaling in the neural crest, where Endothelin signaling functions primarily during development. We further demonstrate that Endothelin induces gene expression through the de-repression of the MADS Box transcription factor MEF2C. Moreover, in the Mef2c gene locus, we identified an Endothelin responsive cis-regulatory element which functions as a central component of an Endothelin-MEF2C positive feedback transcriptional mechanism that regulates downstream gene expression.

2016-11-15 | GSE47919 | GEO

Blocking Fra-1 sensitizes triple-negative breast cancer to olaparib

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Targeting immunosuppressive macrophages overcomes PARP-inhibitor resistance in BRCA1-associated triple-negative breast cancer

Project description:Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.

2021-03-25 | PXD015804 | Pride

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