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Inhibition of Notch4 with Novel Neutralizing Antibodies Reduces Tumor Growth in Multiple Tumor Types and Targets Endothelium and Tumor Associated Macrophages in a Mouse Breast Cancer Model [RiboTag RNA-seq]

ABSTRACT: Inhibition of Notch4 with Novel Neutralizing Antibodies Reduces Tumor Growth in Multiple Tumor Types and Targets Endothelium and Tumor Associated Macrophages in a Mouse Breast Cancer Model [RiboTag RNA-seq]

PROVIDER: PRJNA1009016 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25756137.fastq.gz	Fastqsanger.gz
	SRR25756138.fastq.gz	Fastqsanger.gz
	SRR25756139.fastq.gz	Fastqsanger.gz
	SRR25756140.fastq.gz	Fastqsanger.gz
	SRR25756141.fastq.gz	Fastqsanger.gz

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Inhibition of Notch4 with Novel Neutralizing Antibodies Reduces Tumor Growth in Multiple Tumor Types and Targets Endothelium and Tumor Associated Macrophages in a Mouse Breast Cancer Model [RiboTag RNA-seq]

Project description:Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade reduces tumor vessel function but causes vascular dysfunction, hypoxia, and gastrointestinal toxicity. Notch4 expression is restricted to developing vasculature, where it promotes angiogenesis. Unlike other Notch proteins, Notch4 has rarely been targeted therapeutically. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 in tumor models. E7011 treatment significantly delayed tumor growth and impaired tumor vessel perfusion in mouse models of breast, skin, and lung tumors. In a mouse orthotopic breast cancer model, Notch4 expression was confined to endothelial cells, but E7011 treatment significantly increased tumor-associated macrophages and increased macrophage expression of anti-tumor genes. Liposomal clodronate-mediated macrophage depletion reversed the anti-tumor effects of E7011, demonstrating that Notch4 supports tumor growth via angiocrine signaling to tumor macrophages. We conclude that targeting Notch4 alters tumor vessel function and tumor associated macrophage phenotype, leading to tumor inhibition.

2024-08-08 | GSE241629 | GEO

2024-08-08 | GSE240452 | GEO

Inhibition of Notch4 with Novel Neutralizing Antibodies Reduces Tumor Growth in Multiple Tumor Types and Targets Endothelium and Tumor Associated Macrophages in a Mouse Breast Cancer Model

Project description:Inhibition of Notch4 with Novel Neutralizing Antibodies Reduces Tumor Growth in Multiple Tumor Types and Targets Endothelium and Tumor Associated Macrophages in a Mouse Breast Cancer Model

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Inhibition of Notch4 Using Novel Neutralizing Antibodies Reduces Tumor Growth in Murine Cancer Models by Targeting the Tumor Endothelium.

Project description:Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed in tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancers. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms.SignificanceA first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area.

| S-EPMC11289863 | biostudies-literature

Effect of Notch4 deletion on pancreatic tumorigenesis in mice

Project description:The gene expression of N4-/-PKC (Notch4 -/-; p16fl/fl;LSL-KrasG12D;p48-Cre) mouse pancreatic tumor cell lines was compared to that of PKC ( p16fl/fl; LSL-KrasG12D;p48-Cre) mouse pancreatic tumor cell lines

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Ribotag-based Next Generation Sequencing of tumor-associated astrocytes

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JAG1-NOTCH4 mechanosensing drives atherosclerosis

Project description:Endothelial cell (EC) sensing of fluid shear stress regulates atherosclerosis, a disease of arteries that causes heart attack and stroke. Atherosclerosis preferentially develops at regions of arteries exposed to low oscillatory shear stress (LOSS), whereas high shear regions are protected. We show using inducible EC-specific genetic deletion in hyperlipidaemic mice that the Notch ligands JAG1 and DLL4 have opposing roles in atherosclerosis. While endothelial Jag1 promoted atherosclerosis at sites of LOSS, endothelial Dll4 was atheroprotective. Analysis of porcine and murine arteries and cultured human coronary artery EC exposed to experimental flow revealed that JAG1 and its receptor NOTCH4 are strongly upregulated by LOSS. Functional studies in cultured cells and in mice with EC-specific deletion of Jag1 show that JAG1-NOTCH4 signalling drives vascular dysfunction by repressing endothelial repair. These data demonstrate a fundamental role for JAG1-NOTCH4 in sensing LOSS during disease, and suggest therapeutic targeting of this pathway to treat atherosclerosis.

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A Regulatory T Cell Notch4 Switch Governs Lung Inflammation in Viral Infections

Project description:Coronavirus disease 2019 (Covid19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with lung inflammation and respiratory failure. In a prospective multi-country cohort of Covid19 patients, we found that increased Notch4 expression on circulating Treg cells was associated with increased disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice suppressed the dysregulated innate immune response and rescued disease morbidity and mortality induced by a synthetic analogue of viral RNA or by the influenza H1N1 virus in an amphiregulin-dependent manner. Notably, amphiregulin production declined in Covid19 subjects as a function of disease severity and Notch4 expression. These results identify Notch4 as an immune regulatory switch that licenses virus-induced lung inflammation by altering Treg cell-mediated tissue repair. They also suggest Notch4 as a therapeutic target in Covid19 and other respiratory viral infections.

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A Treg cell Notch4-GDF15 Axis Licenses Tissue Inflammation in Asthma

Project description:Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that IL-6 and STAT3-dependent upregulation of Notch4 on Iung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into TH2 and TH17 effector T (Teff) cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced GDF15 expression in Treg cells, which activated group 2 innate lymphoid cells (ILC2) to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated on circulating Treg cells of asthmatics as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

2020-09-01 | GSE151763 | GEO

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