Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE212316 | GEO | 2022/09/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

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

iRhom2 Promotes Lupus Nephritis through ADAM17-Dependent TNF-α and EGFR Signaling

Project description:Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice; alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of the disease.

2019-01-01 | GSE107705 | GEO

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

Project description: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.

2018-02-19 | GSE107759 | GEO

A Developmentally Prometastatic Niche in Neonatal Liver to Hepatoblastoma mediated by Cxcl1/Cxcr2 Axis

Project description:Hepatoblastoma (HB) is the most common pediatric liver cancer. Its exclusive occurrence in very young children leads us to investigating whether the immature liver provides a protumorigenic niche to HB development. We employed the single-cell RNA-sequencing (sc-RNAseq) to comprehensively profile the HB tumors and their microenvironment in the orthotopic transplantation models established in postnatal day 5 and 60. We demonstrated that the neonatal liver provides a prometastatic niche to HB development via Cxcl1/Cxcr2 axis-mediated HB-aHSC interaction.

2023-01-31 | GSE186027 | GEO

Switching mechanism from AR to EGFR signaling via 3-O-sulfated heparan sulfate in castration-resistant prostate cancer

Project description:Expression of HS3ST1 is markedly upregulated in castration-resistant prostate cancer, which proliferates hormone-independently. In a novel mechanism, EGFR–ERK1/2 signaling is activated via 3-O-sulfated HS and EGF/HB-EGF binding in castration-resistant prostate cancer.

2023-07-20 | GSE223471 | GEO

Selective activation of PERK signaling mediates fibroblast education and tumor progression by a CRELD2-dependent mechanism

Project description:It is now well-accepted that cancers co-opt the microenvironment to support their growth. However, the molecular mechanisms underlying cancer-microenvironment interactions remain poorly defined. We have found that Rho-associated kinase (ROCK) activity in the epithelial component of mammary tumors selectively actuates Protein kinase R-like endoplasmic reticulum kinase (Perk), causing the recruitment and persistent education of tumor-promoting cancer-associated fibroblasts (CAFs), a key component of the cancer microenvironment. Analysis of tumors from mice and human patients identified Cysteine-rich with EGF-like domains 2 (CRELD2), as the paracrine factor underlying PERK-mediated CAF-education downstream of ROCK. CRELD2 expression was found to be regulated by ATF4 downstream of the PERK pathway and knock-down of CRELD2 prevented tumor progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis is a promoter of breast cancer progression and suggesting new therapeutic opportunities.

2020-05-27 | PXD018253 | Pride

GDF15 overexpression dreived from tumor-associated macrophages and cancer cells in the microenvironment of human esophageal squamous cell carcinoma promotes tumor growth and poor prognosis

Project description:Tumor-associated macrophages (TAMs) are known to be involved in progression, angiogenesis and motility of various cancers. We have previously reported the association between increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study roles of TAMs in ESCC, we first exposed peripheral blood monocytes (PBMo) derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of expression of M2 macrophage marker, CD204, and protumorigenic factors, interleukin (IL)-10, VEGFA and MMPs. Next, we compared gene expression profile between PBMo-derived macrophages and PBMo-derived macrophages stimulated with TECM by cDNA microarray. Based on the result, we focused on growth differentiation factor 15 (GDF15) among highly expressed genes including IL-6, IL-8 and CXCL1. Immunohistochemical study on 70 cases of surgically resected ESCCs revealed that GDF15 was detected not only in macrophages but also in cancer cells. High expression of GDF15 in ESCCs was significantly correlated with more malignant phenotypes including lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. Patients with high expression of GDF15 showed poor disease-free survival (p = 0.011) and overall survival (p = 0.041). Furthermore, we found that recombinant human GDF15 promote cell proliferation and phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in tumor microenvironment and is associated with aberrant growth and poor prognosis of human ESCC. We exposed PBMo-derived macrophages from healthy volunteers to TECM and observed their acquisition of TAM-like characters in this study. We further investigated specific cancer-associated gene expression profile in TECM induced TAM-like macrophages by cDNA microarray analysis.

2014-08-01 | E-GEOD-59948 | biostudies-arrayexpress

Comparison of Invasive TAM sub-population to General TAM population

Project description:The tumor microenvironment modifies the malignancy of tumors. In solid tumors this environment is populated by many macrophages (tumor-associated macrophages; TAMs) that in genetic studies that depleted these cells from mouse models of breast cancer were shown to promote tumor progression to malignancy and increase metastatic potential. Mechanistic studies showed that these effects are through the stimulation of tumor cell migration, invasion, intravasation as well as an enhancement of angiogenesis. Using an in vivo invasion assay it was demonstrated that invasive carcinoma cells are a unique sub-population of tumor cells whose invasion and chemotaxis is dependent upon the co-migration of TAMs with obligate reciprocal signaling through an EGF/CSF-1 paracrine loop. In this study these invasion-promoting macrophages were isolated and subjected to analysis of their transcriptome in comparison to TAMs isolated indiscriminately to function using established macrophage markers by flow cytometry. Five biological replicates for each population (Invasive and General TAM) were used.

2010-05-16 | E-GEOD-18295 | biostudies-arrayexpress

Branched-chain ketoacids derived from cancer cells modulate macrophage polarization and metabolic reprogramming

Project description:<p>Macrophages are prominent immune cells in the tumor microenvironment that can be educated into pro-tumoral phenotype by tumor cells to favor tumor growth and metastasis. The mechanisms that mediate a mutualistic relationship between tumor cells and macrophages remain poorly characterized. Here, we have shown <em>in vitro</em> that different human and murine cancer cell lines release branched‐chain α‐ketoacids (BCKAs) into the extracellular milieu, which influence macrophage polarization in an monocarboxylate transporter 1 (MCT1)‐dependent manner. We found that α‐ketoisocaproate (KIC) and α‐keto‐β‐methylvalerate (KMV) induced a pro‐tumoral macrophage state, whereas α‐ketoisovalerate (KIV) exerted a pro‐inflammatory effect on macrophages. This process was further investigated by a combined metabolomics/proteomics platform. KMV and KIC altered macrophage tricarboxylic acid (TCA) cycle intermediates and increased polyamine metabolism. Proteomic and pathway analyses revealed that the three BCKAs, especially KMV, exhibited divergent effects on the inflammatory signal pathways, phagocytosis, apoptosis and redox balance. These findings uncover cancer‐derived BCKAs as novel determinants for macrophage polarization with potential to be selectively exploited for optimizing antitumor immune responses.</p>

2022-10-03 | MTBLS4497 | MetaboLights

Astrocyte-produced HB-EGF limits autoimmune CNS pathology [WGBS]

Project description:Central nervous system (CNS) resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including Multiple Sclerosis (MS). Several studies have demonstrated the involvement of pro- inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from MS patients in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a novel modulator of autoimmune CNS inflammation and potential therapeutic target in MS.

2023-12-01 | GSE245382 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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