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The Notch ligand Jagged1 regulates extracellular matrix production and organization in triple-negative breast cancer

ABSTRACT: The extracellular matrix (ECM) in the tumor microenvironment plays an essential role in the progression of cancer. Here, we show that expression of the Notch ligand Jagged1 correlates with poor patient survival in aggressive breast cancer and that Jagged1 promotes in vivo tumor growth and invasion of triple-negative breast cancer cells. Using transcriptomics, proteomics, and imaging approaches of cancer cell/fibroblast co-cultures, both in vitro and in vivo, we demonstrate that Jagged1 drives fibroblast activation, increased collagen deposition, and aligned organization of ECM fibers. Jagged1 increases transforming growth factor beta (TGFβ) related signaling in fibroblast co-cultures and the Jagged1-induced ECM alignment can be prevented by a TGFβ inhibitor. Thus, Jagged1 regulates ECM remodeling upstream of TGFβ. With the emergence of safe therapeutics targeting specific Notch ligands and receptors, Jagged1 modulation may offer a path to therapeutically target invasive breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296927 | GEO | 2026/02/09

REPOSITORIES: GEO

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JAGGED1 Promotes Tumor Progression through Recruitment of Macrophages and Functional Suppression of Tumor-killing T cells [scRNA-seq]

Project description:Breast cancer is one of the leading causes of cancer-related mortality in women. NOTCH signaling is a well conserved pathway which not only plays critical roles in normal development, but also in cancer progression. One of the Notch ligand, JAGGED1 is overexpressed in about 30% of breast cancer patients. However, the role of JAGGED1 in breast tumorigenesis has not been rigorously examined. By utilizing genetic engineered mouse models of mammary specific Jagged1 expression or knockout, we discover that Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Jagged1 expression leads to increased infiltration of tumor associated macrophages and decreased presentation of T cells within tumor microenvironment. Depletion of macrophages or T cells by neutralizing antibodies diminishes the tumor-promoting effect caused by Jagged1. Mechanistically, Jagged1 activates Notch signaling in tumor cells, leads to increased expression and secretion of multiple cytokines, including IL-6 and WISP. These cytokines help recruit macrophages into the tumor microenvironment. Macrophages crosstalk with infiltrated T cells and inhibit their cytotoxic killing on tumor cells. In triple negative breast cancer patient samples, high expression level of JAGGED1 correlates with increased macrophage infiltration and decreased T cell infiltration within tumor tissues. JAGGED1 also promotes tumor progression in several other solid cancer types, including melanoma, and colon cancer in a T cell dependent manner. Co-administration of immune checkpoint inhibitor, PD-1 antibody with gamma-secretase inhibitor (GSI) significantly inhibits tumor growth. These findings identify a unique oncogenic crosstalk between tumor derived JAGGED1, Macrophages, and T cells to promote tumor progression.

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JAGGED1 Promotes Tumor Progression through Recruitment of Macrophages and Functional Suppression of Tumor-killing T cells [RNA-seq]

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β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects.

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Differential gene expression in Jagged1 treated human dental pulp cells.

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NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence [RNA-Seq]

Project description:We decribe the accessible chormatin landscape in RAS-induced (RIS) and NOTCH induced senescence (NIS) using ATAC-seq. By expressing active NOTCH (N1ICD) in the context of RIS, we find that N1ICD antagonises the formation of accessible regions in RIS. By performing co-cultures, we demonstrate that cells expressing a NOTCH1 ligand, JAGGED1, can antagonise the formation of RIS specific accessible regions.

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NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence [ATAC-Seq]

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NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence [ChIP-Seq]

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Project description:We analyzed specific genes for DNA copy number variation in hepatoma cells and investigated whether these factors are related to liver cancer phenotype. Chromosome 20p, which includes the ligand for Notch pathways, Jagged1, was found to be amplified in several types of hepatoma cells. In conclusion, amplification of Jagged1 contributed to mRNA expression that activates the Jagged1-Notch signaling pathway in liver cancer and led to poor outcome. Comparative genomic hybridization arrays spotted with 1,440 bacterial artificial chromosome clones were used to assess copy number changes in 7 hepatoma cell lines and 2 non-hepatoma cell lines to identify chromosomal regions associated with the pathogenesis of liver cancer.

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