Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE199938 | GEO | 2022/05/16
REPOSITORIES: GEO
Similar Datasets
Project description:The tumor derived Versican (VCAN) can be a possible mediator of the host NF-κB pathway in cancer pathogenesis. In this context, we defined VCAN function in the pathogenesis development in vitro with cell lines as well as in vivo with mouse model. We used the proteomic technique to quantify VCAN integrity and relative abundancy produced by different cancer cell lines and to link this information to our pre-existing data. These results helped us to finalise our dataset and define more clearly VCAN influence tumor development.
2023-05-10 | PXD019883 | Pride
Project description:Type I conventional dendritic cells (cDC1s) are an essential antigen-presenting population, required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli affect cDC1 function remain unclear. Recently, we demonstrated that the cytokine IL-10 inhibits cDC1 maturation induced upon polyinosinic-polycytidylic acid (poly I:C) exposure via a STAT3-dependent mechanism. Furthermore, utilizing a tumor vaccine strategy, we found STAT3 restrains cDC1-mediated anti-tumor immunity. To understand the pathways by which IL-10 and STAT3 regulate cDC1s, we evaluated transcriptional responses by RNA-sequencing. Bioinformatic analyses indicated that many inflammatory pathways were enriched in cDC1s following poly I:C treatment, while interferon (IFN) signaling was uniquely inhibited by STAT3 upon concomitant exposure to IL-10. We found that poly I:C stimulated production of IFN-b and IFN-g from cDC1s. Concurrent exposure to IL-10 suppressed IFN-b and IFN-g secretion as well as accrual of phosphorylated STAT1 and expression of the IFN-response gene Cxcl10 in cDC1s. By contrast, Stat3-deficient cDC1s were refractory to IL-10, indicating STAT3 controls poly I:C-mediated IFN production and IFN transcriptional responses in cDC1s. Moreover, we found that maturation of cDC1s in response to poly I:C is dependent on the type I IFN receptor. Taken together, our data indicate STAT3 is essential for restraining autocrine type I IFN signaling in cDC1s elicited by poly I:C stimulation.
2022-07-26 | GSE188995 | GEO
Project description:<p>The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor-stroma interaction is critically dependent on cell-cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). Here, we show that caveolin-1 (Cav1) is a central modulator of both exosome biogenesis and exosomal protein cargo sorting through the regulation of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets including tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently depose ECM and promote tumor cell invasiveness. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling, but also the generation of distant ECM-enriched stromal niches. These results support a model by which Cav1 is a central regulatory hub for tumor-stroma interactions through a novel exosome-dependent ECM deposition mechanism.</p><p><br></p><p>Linked studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS1977' rel='noopener noreferrer' target='_blank'>MTBLS1977</a></p>
2020-10-07 | MTBLS1969 | MetaboLights
Project description:<p>The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor-stroma interaction is critically dependent on cell-cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). Here, we show that caveolin-1 (Cav1) is a central modulator of both exosome biogenesis and exosomal protein cargo sorting through the regulation of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets including tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently depose ECM and promote tumor cell invasiveness. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling, but also the generation of distant ECM-enriched stromal niches. These results support a model by which Cav1 is a central regulatory hub for tumor-stroma interactions through a novel exosome-dependent ECM deposition mechanism.</p><p><br></p><p>Linked studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS1969' rel='noopener noreferrer' target='_blank'>MTBLS1969</a></p>
2020-10-07 | MTBLS1977 | MetaboLights
Project description:Type-1 conventional dendritic cells (cDC1s) are rare immune cells critical for the induction of antigen-specific cytotoxic CD8+ T-cells. The genetic program driving human cDC1 specification remains largely unexplored. We have previously identified PU.1, IRF8 and BATF3 transcription factors as sufficient to induce cDC1 fate in mouse fibroblasts but reprogramming of human somatic cells was limited by low efficiencies. Here, we investigated single-cell transcriptional dynamics during human cDC1 reprogramming. Human induced cDC1s (hiDCs) generated from embryonic fibroblasts gradually acquire a global cDC1 transcriptional profile and activate antigen presentation signatures. Importantly, other DC subsets are not induced at the single-cell level. We extracted gene modules associated with successful reprogramming and identified inflammatory signaling and the cDC1-inducing transcription factor network as key drivers of the process. Combining IFN-γ, IFN-β and TNF-α with constitutive expression of cDC1-inducing transcription factors lead to improvement of reprogramming efficiency by 190-fold. hiDCs uptake dead cells, secrete inflammatory cytokines and perform antigen cross-presentation, a key cDC1 function. This approach allowed efficient hiDC1 generation from adult fibroblasts and mesenchymal stromal cells. Mechanistically, PU.1 shows dominant and independent chromatin targeting at early phases of reprogramming, recruiting IRF8 and BATF3 to shared binding sites. The cooperative binding at open enhancers and promoters leads to silencing of fibroblast genes and activation of a cDC1 program. These findings provide mechanistic insights into human cDC1 specification and reprogramming and represent a platform for generating patient-tailored cDC1s, a long-sought DC subset for vaccination strategies in cancer immunotherapy.
2022-03-05 | GSE162650 | GEO
Project description:Conventional type 1 dendritic cells (cDC1s) are critical for anti-tumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the anti -tumor functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intratumoral cDC1 maturation using single cell RNA sequencing. We identified NF κB and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-κB or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-κB-dependent IFN-γ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IRF1 in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development new diagnostic and therapeutic approaches to improve cancer immunotherapy.
2021-08-16 | GSE171870 | GEO
Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Currently patients are treated by surgical cytoreductive surgery with the aim of reducing tumor burden to microscopic disease followed by adjuvant combined treatment with a platinum and taxane containing chemotherapy, which affords 80% of patients an initial complete response. However, Abdominal and pelvic recurrence rates are high and response to further chemotherapy is limited. Attempts at introducing biologic therapeutic agents to improve outcome in this disease are ongoing, while prognostic or predictive biomarkers that can stratify patients for treatment are still lacking. Using transcriptome profiling of microdissected tissue samples from high-grade serous ovarian cancer patients, we identified a cancer associated fibroblast (CAF) specific gene signature. Versican, which encodes a extracellular matrix protein, was one of the identified genes which demonstrated up-regulation in cancer stroma. To investigate the function roles, signaling machanism and the effect of versican treatment on ovarian cancer cells, transcriptome profiling of versican treated OVCA433 high-grade serous ovarian cancer cells was performed. High grade serous ovarian cancer cell line OVCA433 was used. Total RNA was isolated from control samples and versican treated cancer cell samples at 48 hours post-treatment followed by cDNA synthesis, IVT and biotin labeling. Samples were then hybridized onto Affymetrix Human genome U133 plus 2.0 microarrays. For each treatment group, three independent samples were prepared for the microarray experiment.
2013-12-31 | E-GEOD-40241 | biostudies-arrayexpress
Project description:functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intratumoral cDC1 maturation using single cell RNA sequencing. We identified NF-κB and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-κB or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-κB-dependent IFN-γ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IRF1 in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development new diagnostic and therapeutic approaches to improve cancer immunotherapy.
2021-08-16 | GSE174089 | GEO
Project description:Matrix induced effects on gene expression in HeLa and MDA-MB-231 cells Tissue homeostasis is dependent on the spatially controlled localization of specific cell types and the correct composition of the extracellular stroma. While the role of the cancer stroma in tumor progression has been well characterized, the specific contribution of the matrix itself is unknown. Furthermore, the mechanisms enabling normal – not cancer – stroma to provide tumor suppressive signals and act as an anti-tumorigenic barrier are poorly understood. Here, we show that extracellular matrix (ECM) generated by normal fibroblasts (NFs) is softer than CAF-matrix and it is the physical and structural features of NF-generated matrix that regulate cancer cell proliferation . We find that normal stromal ECM triggers downregulation and nuclear exit of the histone demethylase JMJD1a resulting in the epigenetic growth restriction of carcinoma cells. Interestingly, JMJD1a positively regulates transcription of many target genes, including YAP/TAZ, and thus therefore gene expression in stiffness-dependent manner. Thus normal stromal restricts cancer cell proliferation through JMJD1a-dependent modulation of gene expression.
2016-08-29 | GSE83366 | GEO
Project description:In this study, we directly compared turkey muscle satellite cell gene expression between satellite cells with the gene versican (VCAN) knocked down by siRNA transfection and those transfected with a lipofectamine control using our 6K Turkey Skeletal Muscle Long Oligo (TSKMLO) microarray (GPL9788). The VCAN gene was previously identified as differentially expressed by genetic line and during development of turkey skeletal muscle (Sporer et al., 2011). Gene expression changes were investigated in satellite cells after 72 h of proliferation and after 48 h of differentiation. We identified novel candidate genes and pathways as playing potentially crucial roles in the VCAN-mediated effects on the normal processes of proliferation and differentiation in turkey satellite cells previously identified by Velleman et al. (submitted). This experiment was designed to investigate the role of VCAN expression in turkey satellite cells during two crucial processes in muscle development: proliferation and differentiation. Satellite cells were isolated from 7-week-old turkeys from the RBC2 line. Cells were transfected with either VCAN siRNA or a lipofectamine control; VCAN expression was knocked down by over 50% with siRNA transfection (Velleman et al., submitted). Satellite cells were then induced to proliferate for 72h or differentiate for 48h; culture plates from each stage (n=4) were frozen until RNA extraction. Microarrays directly compared the VCAN-knockdown to control from each of 4 culture plates and utilized a dye swap to equal 8 arrays for each of the cell developmental stages, proliferation and differentiation, and 16 arrays for the overall experiment investigating the role of VCAN expression in satellite cell development and function. Hybridizations were performed in random order.
2012-05-31 | E-GEOD-36365 | biostudies-arrayexpress