Effect of Notch4 deletion on pancreatic tumorigenesis in mice
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ABSTRACT:
PROVIDER: PRJNA762919 | ENA |
REPOSITORIES: ENA
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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
2023-03-20 | GSE184060 | GEO
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.
2022-09-06 | GSE206117 | GEO
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.
2020-11-01 | GSE159584 | GEO
Project description:Combined deletion of MEN1, ATRX and PTEN triggers pancreatic neuroendocrine tumorigenesis in mice
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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.
2022-09-06 | GSE207275 | GEO
Project description:IL-17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. The cellular compartment and downstream molecular mediators of IL-17-mediated pancreatic tumorigenesis have not been fully identified. We interrogated the cellular compartment required by generating transgenic animals with Interleukin 17 receptor A (IL-17RA) genetically deleted from the pancreatic epithelial compartment vs. the hematopoietic compartment via generation of IL-17RA-deficient (IL17-RA-/-) bone marrow chimeras, in the context of embryonically activated or inducible Kras. Deletion of IL-17RA from the pancreatic epithelial compartment, but not from hematopoietic, resulted in delayed premalignant lesions initiation and progression and increased CD8+ cytotoxic T cells infiltration to the tumor microenvironment. Absence of IL-17RA in the pancreatic compartment affected transcriptional profiles of epithelial cells, modulating stemness and immunological pathways. Interestingly, B7-H4, a known inhibitor of T cell activation encoded by the gene Vtcn1, was the most upregulated checkpoint molecule via IL17 early during pancreatic tumorigenesis, and its genetic deletion delayed pancreatic premalignant lesions development and reduced immunosuppression. We reveal pancreatic epithelial IL-17RA requirement for pancreatic tumorigenesis by reprogramming the immune pancreatic landscape which is partially orchestrated by regulation of B7-H4.
2024-04-15 | GSE264054 | GEO
Project description:Expression of the Notch family of receptors is often upregulated in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on Notch4, which had not been investigated in PDAC. We generated KC (LSL-KrasG12D;p48-Cre), N4 - / - KC (Notch4- / -;LSL-KrasG12D;p48-Cre), PKC (p16fl/fl;LSL-KrasG12D;p48-Cre), and N4 - / - PKC (Notch4-/ -; p16fl/f l;LSL-KrasG12D;p48-Cre) genetically engineered mouse models (GEMM). We performed caerulein treatment in both KC and N4 - / - KC mice, and the development of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions were significantly diminished in the N4 - / - KC than in the KC GEMM (P = 0.01). This in vivo result was validated by in vitro ADM induction of the explant cultures of pancreatic acinar cells from the N4 - / - KC and KC mice (P < 0.001), confirming that Notch4 is an important contributor to early pancreatic tumorigenesis. To evaluate the role of Notch4 in the later stage of pancreatic tumorigenesis, we compared the PKC and N4 - / - PKC mice. The N4 - / - PKC mice had better overall survival (P = 0.012) and significantly reduced tumor burden (PanIN: P = 0.018 at 2 months, PDAC: P = 0.039 at 5 months) compared with the PKC GEMM. RNA-sequencing analysis of pancreatic tumor cell lines derived from the PKC and N4 - / - PKC GEMMs revealed that 408 genes were differentially expressed (FDR < 0.05) and Pcsk5 is a potential downstream effector of the Notch4 signaling pathway (P < 0.001). Low expression of Pcsk5 positively correlates with good survival in patients with PDAC (P = 0.028). We have identified a novel role for Notch4 signaling with tumor-promoting function in pancreatic tumorigenesis. Our study also uncovered a novel association between Pcsk5 and Notch4 signaling in PDAC.SignificanceWe demonstrated that global inactivation of Notch4 significantly improved the survival of an aggressive mouse model for PDAC and provided preclinical evidence that Notch4 and Pcsk5 are novel targets for PDAC therapies.
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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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