Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer

ABSTRACT: Interleukin (IL)-11 is a member of the IL-6 family of cytokines and involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generated Il11 reporter mice. IL-11+ cells appeared in the colon of murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuated the development of colitis-associated colorectal cancer. IL-11+ cells expressed fibroblast markers, and genes associated with cell proliferation and tissue repair. IL-11 induced the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis revealed that a set of genes enriched in IL-11+ fibroblasts was elevated in human colorectal cancer, and correlated with reduced recurrence-free survival. Together, IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed forward loop between tumor cells and fibroblasts in the tumor microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE164232 | GEO | 2021/02/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Characterization of Interleukin 11-producing fibroblasts that constitute a niche for tumor development [Agilent]

Project description:Interleukin (IL)-11 belongs to a member of the IL-6 family of cytokines and is involved in a variety of cellular responses. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generated Il11 reporter mice. IL-11+ cells rapidly appeared in the colon of mice after dextran sulfate sodium treatment. IL-11+ cells expressed fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11+ cells also appeared in the colon of three murine tumor models and human colorectal cancers. Deletion of Il11ra1 or Il11 attenuated the development of colitis-associated colorectal cancers in mice. IL-11 induced STAT3 phosphorylation in colonic fibroblasts, and injection of IL-11 receptor agonist upregulated many genes that were enriched in IL-11+ cells. Together, tumor cells induced IL-11+ fibroblasts, and a feed-forward loop between IL-11 and IL-11+ fibroblasts might constitute a niche for promoting tumor development.

2021-02-22 | GSE141643 | GEO

IL-11 is a crucial determinant of cardiovascular fibrosis (mouse single cell)

Project description:Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging–genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signaling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.

2017-12-11 | GSE107909 | GEO

Loss of colonic primary cilia promotes inflammation and carcinogenesis

Project description:Primary cilia (PC) are important signaling hubs in cells and we explored their role in colorectal cancer (CRC) and colitis. In the colon we found PC to be mostly present on different subtypes of fibroblasts and exposure of mice to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced acute colitis decreased PC numbers. We employed conditional knock-out strains for the PC essential genes, Kif3A and Ift88, to generate mice with reduced numbers of PC on colonic fibroblasts. These mice showed an increased susceptibility in the CAC model as well as in DSS-induced colitis. Secretome and immunohistochemical analyses of DSS-treated mice displayed an elevated production of the pro-inflammatory cytokine IL-6 in PC-deficient colons. An inflammatory environment diminished PC presence in primary fibroblast cultures. This was triggered by IL-6 as identified by RNAseq analysis together with blocking experiments, suggesting an activation loop between IL-6 production and PC loss. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC.

2022-11-29 | PXD033440 | Pride

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration [scRNA-Seq]

Project description:Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT2 and AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing (scRNA-seq) datasets of human interstitial lung disease, we found that Interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ epithelial cells and basaloid cells. Stimulation of AT2 cells and distal airway epithelial cells with IL11 or TGFβ1 caused epithelial-to-mesenchymal transition (EMT), induced extracellular matrix (ECM) production, increased KRT8 expression and stalled AT2-to-AT1 differentiation, with TGFβ1 effects being partially IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived Krt8+ transitional cells and deletion of Il11ra1 in AT2 lineage cells prevented the accumulation of Krt8+ transitional cells, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11 antibodies. scRNA-seq analysis of lung epithelial cells from mice with deletion of Il11ra1 in AT2 lineage cells further identified the importance of IL11 signaling for the potentiation and polarization of a disease-causing, ECM producing KRT8+ transitional cells that contributes to pathological lung remodeling. Overall, our data show that IL11 maintains damaged AT2 cells in a transitional state, impairs reparative AT1 differentiation and impairs endogenous alveolar regeneration to cause fibrotic lung disease.

2024-08-12 | GSE261793 | GEO

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration [RNA-seq]

2024-08-12 | GSE218386 | GEO

IL-11 is a therapeutic target in idiopathic pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here we show that IL-11 is upregulated in the lung of IPF patients, associated with disease severity and is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive, ACTA2+ve, collagen secreting myofibroblasts, in an ERK-dependent fashion. In mice, fibroblast-specific transgenic expression or administration of Il-11 drives lung fibroblast-to-myofibroblast transformation and causes lung fibrosis. Il11ra1 deleted mice, whose lung fibroblasts are unresponsive to pro-fibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11 neutralising antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment both prevented and reversed lung fibrosis, which was accompanied by diminished Erk activation. These data prioritise IL-11 as a drug target for lung fibrosis and IPF.

2022-05-06 | GSE130983 | 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

Critical conditions for studying Interleukin-11 signalling in vitro and avoid experimental artefacts

Project description:Interleukin (IL) 11 is upregulated in a number of fibro-inflammatory diseases and cancer, where it binds the cognate IL11 receptor alpha subunit (IL11RA) to form a hexameric IL11:IL11RA:gp130 signalling complex. Primary cells such as hepatic stellate cells, fibroblasts, and hepatocytes are ideal experimental systems to study IL11 signalling in vitro. In contrast to immortalized cell lines, primary cells better capture physiologically relevant cellular physiology and pathobiology. This collection of protocols details experimental and culturing conditions for primary cells that preserve meaningful cellular states and physiological responses ex vivo in conventional 2D cell culture systems. Our data suggest that cell type, cell culture conditions, passage number, concentrations of stimuli, timing, and other factors have major implications for studies of IL11 signalling. In vitro experiments with primary cell material need to be planned and executed with great caution. Otherwise, physiologically relevant mechanisms may become dysfunctional, and reproducible experimental artefacts can obscure our view of true cytokine biology.

2021-09-28 | GSE180652 | GEO

Genome-wide analysis of interleukin (IL) -6 and IL-11 responsive genes in murine gastric tumors

Project description:We performed micrarrays to analyse gene expression in spontaneously arising gastric tumors from gp130Y757F/F mutant mice (Tebbutt et al., 2002) following administration of recombinant human IL-6 or IL-11. The present study was designed to assess differences in gene expression in response to IL-6 and IL-11, two cytokines which both activate the shared gp130 receptor and downstream Stat3 signalling pathway. Since gastric tumorigenesis in gp130Y757F/F mice is strictly dependent on IL-11, but not IL-6 signalling (Ernst et al., 2008) the study aimed to identify IL-6 and IL-11 specific target genes which may account for the IL-11 dependent tumor development. Total RNA was obtained from gastric tumor tissue of gp130Y575F/F mice collected 60 min after a single systemic (i.p.) administration of PBS (vehicle control), recombinant human IL6 or IL11 (5 ug). The gene expression profile of the IL-6 and IL-11 treated samples were separately compared to the PBS (vehicle) treated control samples, resulting in two lists of responsive genes (”IL-6 vs control” and “IL-11 vs control”).

2013-08-10 | E-GEOD-43800 | biostudies-arrayexpress

Gene expression profiling of colitis-associated and sporadic colorectal tumors in mice

Project description:To uncover molecular mechanisms specifically involved in the pathogenesis of colitis-associated colon cancer (CAC), we studied tumorigenesis in experimental models of CAC and sporadic CRC that mimic characteristics of human CRC. Using comparative whole genome expression profiling, we observed differential expression of epiregulin (Ereg) in mouse models of colitis-associated, but not sporadic colorectal cancer. Similarly, highly significant upregulation of Ereg expression was found in cohorts of patients with colitis-associated cancer in inflammatory bowel disease but not in sporadic colorectal cancer. Furthermore, tumor-associated fibroblasts were identified as major source of Ereg in colitis-associated neoplasias. Functional studies showed that Ereg-deficient mice, although more prone to colitis, are strongly protected from colitis-associated tumors, and data from serial endoscopic studies revealed that Ereg promotes growth rather than initiation of tumors.

2013-04-01 | GSE43338 | GEO

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