The CD200-CD200R axis promotes squamous cell carcinoma metastasis via regulation of Cathepsin K
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA739217 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The CD200-CD200R immunoregulatory signaling axis plays an etiological role in the survival and spread of numerous cancers primarily through suppression of anti-tumor immune surveillance. Our previous work outlined a pro-metastatic role for the CD200-CD200R axis in cutaneous squamous cell carcinoma (cSCC) that is independent of direct T cell suppression but modulates the function of infiltrating myeloid cells. To identify effectors of the CD200-CD200R axis important for cSCC metastasis, we conducted RNA-Seq profiling of infiltrating CD11b+Cd200r+ cells isolated from Cd200+ versus Cd200 null cSCCs and identified the cysteine protease Cathepsin K (Ctsk) to be highly upregulated in Cd200+ cSCCs. CD11b+Cd200r+ cells, which expressed phenotypic markers associated with myeloid-derived suppressor cell-like cells and tumor-associated macrophages, were the primary source of Ctsk expression in cSCC. Using a Cd200r+ myeloid cell-cSCC co-culture system, we observed that induction of Ctsk in Cd200r+ tumor-infiltrating cells was dependent on engagement of the CD200-CD200R axis, indicating that Ctsk is a target gene of this pathway in the cSCC tumor microenvironment. Inhibition of Ctsk, but not matrix metalloproteinases (MMPs), significantly blocked cSCC cell migration through collagen gels in vitro. Finally, both targeted Cd200 disruption in tumor cells and Ctsk pharmacological inhibition dramatically reduced cSCC metastasis in vivo. Collectively, our findings identify a novel direct role for Cd200r+ infiltrating myeloid lineages in tumor metastasis and support the conclusion that CD200 stimulates cSCC invasion and metastasis via induction of Ctsk in CD200r+ infiltrating cells.
2021-06-19 | GSE178496 | GEO
Project description:Mouse back skin was disassociated to single cells, sorted by cell surface markers and tested by microarrray To compare the gene expression of mouse bulge (CD34+CD200+CD49+) versus secondary hair germ (CD34-CD200+CD49+) versus interfollicular epidermis (CD34-CD200-CD49+) xx Bald scalp retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells Androgenetic alopecia (AGA) or common baldness results from a marked decrease in hair follicle size. This miniaturization may be related to loss of hair follicle stem or progenitor cells. To test this hypothesis, we analyzed bald and non-bald scalp from the same individuals for the presence of hair follicle stem and progenitor cells using flow cytometry to quantitate cells expressing CYTOKERATIN 15 (KRT15), CD200, CD34 and ALPHA-6-INTEGRIN (ITGA6). High levels of KRT15 expression correlated with stem cell properties of small cell size and quiescence. Cells with the highest level of KRT15 expression were maintained in bald scalp; however, distinct populations of CD200high ITGA6high cells and CD34-positive cells were markedly diminished. Consistent with a progenitor cell phenotype, the diminished populations localized closely to the stem-cell rich bulge area but were larger and more proliferative than the bulge stem cells. In functional assays, analogous CD200 high /Itga6 high cells from murine hair follicles were multipotent and generated new hair follicles in skin reconstitution assays. These findings suggest that a defect in stem cell activation plays a role in the pathogenesis of AGA. 4 independent biologic replicates (each pooled from 3 distinct mice) were sorted for Mouse bulge (CD34+CD200+CD49+) versus secondary hair germ (CD34-CD200+CD49+) versus interfollicular epidermis (CD34-CD200-CD49+)
2011-01-12 | E-GEOD-21568 | biostudies-arrayexpress
Project description:Tumor-associated macrophages (TAMs) have emerged as prominent cells within the tumor microenvironment playing critical roles in extracellular matrix remodeling, tumor cell proliferation and invasion, angiogenesis, and metastasis. Cathepsin proteases, produced by tumor cells and TAMs, have been demonstrated to mediate these processes, but it still remains unclear how these typically lysosomal enzymes are capable of executing their functions in the extracellular space. Here we identify a novel interaction between STAT6 and STAT3 that potently upregulates cathepsin secretion in macrophages in response to TH2 cytokine stimulation. Systematic gene expression analyses reveal that the TH2 cytokine IL-4 synergizes with IL-6 or IL-10 to activate the IRE1α/ XBP1 axis of the unfolded protein response. Pharmacological inhibition of the IRE1α axis blunts cathepsin secretion in macrophages and blocks macrophage-mediated tumor cell invasion. Finally, we show that genetic ablation of either STAT6 or STAT3 signaling impairs tumor development and invasion. Thus, these findings demonstrate that TH2 cytokine-mediated STAT6 and STAT3 activation in macrophages promotes a professional secretory phenotype capable of enhancing tumor cell invasion in a cathepsin-dependent manner.
2016-08-17 | GSE70626 | GEO
Project description:Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca+2) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis. Here we describe the presence of massive regulation of Ca+2 responsive genes in sCJD brain tissue, accompanied by two Ca+2-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons. Additionally, massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca+2 homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model. Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.
2017-05-15 | GSE90977 | GEO
Project description:Human hair follicles from normal areas of the scalp were disassociated to single cells, sorted and tested by microarrray To compare the expression of human CD200+ CD49+ hair follicle keratinocytes versus CD200-CD49+ keratinocytes
2011-01-12 | GSE21567 | GEO
Project description:Mouse back skin was disassociated to single cells, sorted by cell surface markers and tested by microarrray To compare the gene expression of mouse bulge (CD34+CD200+CD49+) versus secondary hair germ (CD34-CD200+CD49+) versus interfollicular epidermis (CD34-CD200-CD49+) xx Bald scalp retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells Androgenetic alopecia (AGA) or common baldness results from a marked decrease in hair follicle size. This miniaturization may be related to loss of hair follicle stem or progenitor cells. To test this hypothesis, we analyzed bald and non-bald scalp from the same individuals for the presence of hair follicle stem and progenitor cells using flow cytometry to quantitate cells expressing CYTOKERATIN 15 (KRT15), CD200, CD34 and ALPHA-6-INTEGRIN (ITGA6). High levels of KRT15 expression correlated with stem cell properties of small cell size and quiescence. Cells with the highest level of KRT15 expression were maintained in bald scalp; however, distinct populations of CD200high ITGA6high cells and CD34-positive cells were markedly diminished. Consistent with a progenitor cell phenotype, the diminished populations localized closely to the stem-cell rich bulge area but were larger and more proliferative than the bulge stem cells. In functional assays, analogous CD200 high /Itga6 high cells from murine hair follicles were multipotent and generated new hair follicles in skin reconstitution assays. These findings suggest that a defect in stem cell activation plays a role in the pathogenesis of AGA.
2011-01-12 | GSE21568 | GEO
Project description:Lung cancer is an intrinsically highly metastatic disease and the leading cause of cancer-related deaths worldwide. Although discovery of molecular aberrations in lung adenocarcinomas has led to development of effective targeted therapies, corresponding “drivers” in lung squamous carcinomas (LUSC) have not materialized. Extensive molecular profiling has revealed LUSC tumors have non-recurrent somatic mutations and are largely driven by copy number alterations. Because microRNAs (miRs) play increasingly important roles in regulating metastasis-relevant pathways, we evaluated whether miRs can regulate LUSC progression. By integrating bioinformatics of the Cancer Genome Atlas (TCGA) with novel, highly metastatic LUSC models, we found that miR-671-5p is a key inhibitor of LUSC metastasis. Surprisingly, miR-671-5p regulates LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of CDR1as is through miR-7 sponging, we found miR-671-5p more potently silences an axis of CDR1as and its anti-sense transcript, cerebellar degeneration related antigen 1 (CDR1). To our knowledge, no function of CDR1 has ever been described. We found loss of CDR1as and CDR1 significantly inhibited LUSC metastases. Intriguingly, CDR1 was strongly associated with an epithelial-mesenchymal transition (EMT) program in LUSC tumors, and was sufficient to promote metastases, increased migration and substrate-independent survival, known as anoikis-resistance. CDR1, which directly interacts with AP1 and COPI subunits, no longer promoted migration and anoikis-resistance upon blockade of Golgi trafficking. Our findings reveal a miR/circRNA axis that regulates LUSC metastases through an enigmatic protein, CDR1.
2021-09-08 | PXD012286 | Pride
Project description:Purpose: Understanding immunosuppression in AML is critical . The goals of this study are to compare the transcriptomics of human CD3+ T cells from humanized mice exposed to CD200+/- AML. Methods: NSG mice were humanized with 10x10^6 healthy PBMCs prior to the introduction of CD200+ or CD200- OCI-AML3 cells. After 10 days, CD3+ T cells were isolated and RNA was sequenced. Results: T cells from mice with CD200+ AML were characterized by an enrichment of T cell activation pathways and a downregulation of numerous metabolic pathways, including OXPHOS and glycolysis. Conclusions: Our results demonstrate, for the first time, that CD200+ AML can directly impair T cell metbolism.
2021-04-24 | GSE173194 | GEO
Project description:To explore metastasis-related genes in high-metastatic cells (HOC313-LM), we performed gene expression array analysis with HOC313-LM and HOC313-Parent (HOC313-P). Moreover, to identify metastasis-related signaling pathway, gene expression profiles of each of transplanted tumor tissues in the primary site or in the metastatic site were analyzed by systems biology analysis and Ingenuity Pathway Analysis (IPA; Ingenuity Systems, Inc., Redwood City, CA). As a result, RhoA signaling pathway emerged as the critical molecular pathway in the metastatic tumor compared to the primary tumor. Identification of metastasis-related genes and metastasis-related pathway in squamous cell carcinoma Extraction of difference of gene expression level between high-metastatic subline (HOC313-LM) and low-metastatic subline (HOC313-P)
2016-03-03 | E-GEOD-62636 | biostudies-arrayexpress
Project description:Clostridioides difficile CD200 Genome sequencing and assembly
| PRJNA85775 | ENA