Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ADAM17 is required for EGF-R induced intestinal tumors via IL-6 trans-signaling

ABSTRACT: Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R) but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited and the few remaining tumors were of low grade dysplasia. RNA-Seq analysis demonstrated downregulation of STAT3 and Wnt pathway components. Since EGF-R on myeloid cells, but not on intestinal epithelial cells is required for intestinal cancer and IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally inhibited in IL-6 -/- and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R-mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces ß-catenin dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer, which could circumvent intrinsic and acquired resistance to EGF-R blockade.

ORGANISM(S): Mus musculus

PROVIDER: GSE107759 | GEO | 2018/02/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ADAM17 is required for EGF-R induced intestinal tumors via IL-6 trans-signaling

Project description:ADAM17 is required for EGF-R induced intestinal tumors via IL-6 trans-signaling

| PRJEB23659 | ENA

ADAM17 is required for EGF-R induced intestinal tumors via IL-6 trans-signaling

Project description:ADAM17 is required for EGF-R induced intestinal tumors via IL-6 trans-signaling

| PRJNA421311 | ENA

Blockade of the Protease ADAM17 Ameliorates Experimental Pancreatitis

Project description:Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalisation, including death. Despite the global health burden of pancreatitis, currently there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumour necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signalling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17ex/ex mice – which are homozygous for the hypomorphic Adam17ex allele resulting in marked reduction in ADAM17 expression – and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-week) and chronic (20-weeks) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was upregulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (Adam17ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor; A17pro) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signalling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, upregulation of the ADAM17/IL-6 trans-signalling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.

2022-10-06 | GSE214666 | GEO

Epidermal growth factor shedding directs macrophage education in cancer

Project description:Macrophages in the tumor microenvironment have a significant impact on tumor progression. Depending on the signaling environment in the tumor, macrophages can either support or constrain tumor growth and metastasis. It is therefore of therapeutic interest to identify the tumor-derived factors that control macrophage education. With this aim, we correlated the expression of ADAM proteases, which are key mediators of cell-cell signaling, to the expression of pro-tumorigenic macrophage markers in human cancer cohorts. We identified ADAM17, a sheddase upregulated in many cancer types, as a protein of interest. Depletion of ADAM17 in cancer cell lines reduced the expression of several pro-tumorigenic markers in neighboring macrophages in vitro as well as in mouse tumor models. Accordingly, ADAM17-/- educated macrophages demonstrated a reduced ability to induce cancer cell invasion. Using quantitative mass spectrometry-based proteomics, we identified HB-EGF, shed by ADAM17 in the cancer cells, as the implicated molecular mediator of macrophage education. Additionally, RNA-seq and ELISA experiments revealed that ADAM17-dependent HB-EGF release induces the expression and secretion of CXCL chemokines in macrophages, which in turn stimulates cancer cell invasion. In conclusion, we provide evidence that ADAM17 mediates a paracrine HB-EGF-chemokine feedback loop, whereby cancer cells hijack macrophages to promote tumor progression.

2022-09-18 | PXD030740 | Pride

ADAM17-mediated EGFR ligand shedding directs macrophage-promoted cancer cell invasion

Project description:Macrophages in the tumor microenvironment have a substantial impact on tumor progression. Depending on the signaling environment in the tumor, macrophages can either support or constrain tumor progression. It is therefore of therapeutic interest to identify the tumor-derived factors that control macrophage education. With this aim, we correlated the expression of A Disintegrin and Metalloproteinase (ADAM) proteases, which are key mediators of cell-cell signaling, to the expression of protumorigenic macrophage markers in human cancer cohorts. We identified ADAM17, a sheddase upregulated in many cancer types, as a protein of interest. Depletion of ADAM17 in cancer cell lines reduced the expression of several protumorigenic markers in neighboring macrophages in vitro as well as in mouse models. Moreover, ADAM17–/– educated macrophages demonstrated a reduced ability to induce cancer cell invasion. Using mass spectrometry–based proteomics and ELISA, we identified HB-EGF and AREG, shed by ADAM17 in the cancer cells, as the implicated molecular mediators of macrophage education. Additionally, RNA-Seq and ELISA experiments revealed that ADAM17-dependent HB-EGF ligand release induced the expression and secretion of CXCL chemokines in macrophages, which in turn stimulated cancer cell invasion. In conclusion, we provide evidence that ADAM17 mediates a paracrine EGFR-ligand-chemokine feedback loop, whereby cancer cells hijack macrophages to promote tumor progression.

2022-09-02 | GSE212316 | GEO

Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2

Project description:The N-Myc Downstream-Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4-/-) CRC models and an in-direct co-culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that absence of Ndrg4 does not trigger any functional or morphological GI-abnormalities. However, combining in vivo, in vitro and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4-/- ENS cell secretome, which is enriched for Nidogen-1 (Nid1) and Fibulin-2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance tumorigenic capacities of CRC cells and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS-derived Nidogen-1 and Fibulin-2 enhance colorectal carcinogenesis.

2021-04-23 | PXD024502 | Pride

Maslinic acid-enriched diet decreases intestinal tumorigenesis in Apc(Min/+) mice through transcriptomic and metabolomic reprogramming

Project description:Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in Apc(Min/+) mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the Apc(Min/+) mice model, suggesting its chemopreventive potential against colorectal cancer.

2017-02-09 | MTBLS240 | MetaboLights

An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc-mutation-driven intestinal tumorigenesis

Project description:Interleukin-25 and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection, and are associated with inappropriate allergic reactions. Recently, it was reported that IL-33-activated ILC2s augment protective tissue-specific pancreatic cancer immunity. Here we show a diametrically opposite role for intestinal IL-25-activated ILC2s where they create an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression have reduced survival, and increased IL-25 Rexpressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired anti-tumor responses. Ablation of IL-25-signalling reduced tumors, virtually doubling life-expectancy in an Apc-mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promotes tumor ILC2s, which sustain MDSCs to suppress anti-tumor immunity. Therapeutic blockade of IL-25-signalling decreased ILC2s, MDSCs and adenoma/adenocarcinoma, while increasing anti-tumor IFNg and adaptive T cell immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33, and ILC2s in cancer cannot be generalized, and instead offer differential pathways for therapeutic intervention.

2022-04-20 | GSE199113 | GEO

Gene expression profiling of fibroblast subpopulations (COLVI+ vs. COLVI-) in mice

Project description:Functional studies using genetically modified mice with COLVI-specific STAT3 loss- or gain-of function demonstrated a critical role of STAT3 activation through IL-6 and IL-11 in fibroblasts during colorectal tumorigenesis in vivo. To reveal molecular mechanism specifically involved the STAT3 driven colorectal cancer development, we performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblasts subpopulations (COLVI+ vs. COLVI-) upon STAT3 activation under different conditions (IL-6 vs. IL-11) uncovering the regulation of transcriptional patterns associated with fibroblast activation, cytokine signaling and angiogenesis.

2020-01-27 | E-MTAB-7764 | biostudies-arrayexpress

Development of a proteomic workflow for the identification of heparan sulfate proteoglycan-binding substrates of ADAM17

Project description:Ectodomain shedding, which is the proteolytic release of transmembrane proteins from the cell surface, is crucial for cell-to-cell communication and other biological processes. The metalloproteinase ADAM17 mediates ectodomain shedding of over 50 transmembrane proteins ranging from cytokines and growth factors, such as TNF and EGFR ligands, to signaling receptors and adhesion molecules. Yet, the ADAM17 sheddome is only partly defined and biological functions of the protease have not been fully characterized. Some ADAM17 substrates (e.g. HB-EGF) are known to bind to heparan sulfate proteoglycans (HSPG), and we hypothesised that such substrates would be under-represented in traditional secretome analyses, due to their binding to cell surface or pericellular HSPGs. Thus, to identify novel HSPG-binding ADAM17 substrates, we developed a proteomic workflow that involves addition of heparin to solubilize HSPG-binding proteins from the cell layer, thereby allowing their mass spectrometry detection by heparin-secretome (HEP-SEC) analysis. Applying this methodology to murine embryonic fibroblasts stimulated with an ADAM17 activator enabled us to identify 47 transmembrane proteins that were shed in response to ADAM17 activation. This included known HSPG-binding ADAM17 substrates (i.e. HB-EGF, CX3CL1) and 14 novel HSPG-binding putative ADAM17 substrates.

2024-10-15 | PXD055223 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data