Targeting the MAtrix REgulating MOtif, MAREMO, abolishes hallmarks of cancer
Ontology highlight
ABSTRACT:
INSTRUMENT(S): NextSeq 2000
ORGANISM(S): Mus musculus
SUBMITTER: Raphael Carapito
PROVIDER: E-MTAB-13677 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Tenascin-C (TNC), a cancer-associated extracellular matrix glycoprotein, plays a pivotal role in tumor growth. However, the mechanism whereby TNC affects tumor biology remains unclear. We used microarrays to investigate change in global gene expression between tumors in wild-type (WT) mice, which express TNC, and tumors in TNC-knockout (TNKO) mice. We developed a non-TNC-producing mouse mammary tumor cell line (GLMT1). GLMT1 was inoculated in the drosal flank of WT mice and TNKO mice. After 14 days, the tumor were harvested and RNA was extracted. Subsequently, they were processed and hybridized on Affymetrix GeneChip Mouse Genome 430 2.0 Array
2016-02-10 | E-GEOD-77739 | biostudies-arrayexpress
Project description:The tumor stroma is believed to contribute to some of the most malignant characteristics of epithelial tumors. However, signaling between stromal and tumor cells is complex and remains poorly understood. Here we show that genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumors. Global gene expression profiling in mammary stromal cells identified a Pten-specific signature associated with massive extra-cellular matrix (ECM) remodeling, innate immune cell infiltraion and increased angiogenesis. Execution of this transcriptional program was mediated, in part, by the induction, phosphorylation and recruitment of Ets2 to target promoters. Remarkably, Ets2 inactivation in Pten stroma-deleted tumors was sufficient to decrease tumor growth and progression. These findings identify the Pten-Ets2 axis as a critical stroma-specific signaling pathway that suppresses mammary epithelial tumors. Experiment Overall Design: Wild type and Pten null primary mammary fibroblasts isolated from 8 week old female mice were cultured, RNA was extracted and Affymetrix gene expression arrays were performed.
2009-11-10 | E-GEOD-16073 | biostudies-arrayexpress
Project description:In the tumor microenvironment the extracellular matrix molecule tenascin-C is highly expressed which correlates with worsened survival prognosis. Tenascin-C promotes multiple steps in cancer progression. In particular, tenascin-C promotes the tumor angiogenic switch and the formation of more but poorly functional blood vessels by ill defined mechanisms. Here, we studied tenascin-C angio-modulatory functions by tumor and stromal cells. Unexpectedly, we observed that direct contact of endothelial cells with tenascin-C impairs angiogenesis through disruption of actin polymerization. This resulted in cytoplasmic retention of the F-actin sensor and co-transcription factor YAP and led to downregulation of YAP pro-angiogenic target genes. Conversely, tumor cells and carcinoma associated fibroblasts exposed to tenascin-C secreted pro-angiogenic factors that promoted endothelial cell survival and tubulogenesis. We identified and functionally validated CXCL12 and Ephrin- B2 as important pro-angiogenic effectors of tenascin-C. Proteomic analysis of the secretome of tumor cells exposed to tenascin-C revealed a signature that predicts shorter survival of patients with low grade glioma and glioblastoma with a particular significance for a combined expression of tenascin-C and Ephrin-B2. Altogether, we demonstrated a dual mechanism of action of tenascin-C in tumor angiogenesis where direct contact of endothelial cells with tenascin-C impairs angiogenesis, and paracrine signals derived from contact of tumor cells and carcinoma associated fibroblasts with tenascin-C promotes angiogenesis. These opposing effects provide for the first time an explanation of divergent mechanisms controlled by tenascin-C which can result in a denser but less functional tumor blood vasculature and might unveil new targeting and prediction opportunities.
2016-11-07 | PXD005217 | Pride
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:<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:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.
2018-02-07 | PXD007909 | Pride
Project description:TRAIL cytotoxicity is exploited as anti-cancer therapy since many years, however incomplete knowledge is generating many obstacles. Here, we address whether the highly abundant extracellular matrix molecule tenascin-C (TNC) orchestrating an immune suppressive tumor microenvironment and binding TRAIL impacts TRAIL cytotoxicity. We used an immune competent autologous NT193 breast cancer model with a knockdown (KD) of Tnfsf10 (encoding TRAIL) and observed accelerated tumor growth marked by less apoptosis, more proliferation and less myeloid cell infiltration as seen by flow cytometry. Grafting the same Tnfsf10 KD cells into a TNC knockout host showed repressed tumor growth suggesting that TNC is involved in regulating TRAIL functions.
2024-05-30 | E-MTAB-14089 | biostudies-arrayexpress
Project description:Younger age and obesity increase the incidence and rates of metastasis of triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. The tissue microenvironment, specifically the extracellular matrix (ECM), is known to promote tumor invasion and metastasis. We sought to characterize the effect of both age and obesity on the ECM of mammary fat pads. We used a diet-induced obesity (DIO) model where 10-week-old female mice were fed a high-fat diet (HFD) for 16 weeks or a control chow diet (CD) where time points were every 4 weeks to monitor age and obesity HFD progression. We isolated the mammary fat pads to characterize the ECM at each time point. Utilizing proteomics, we found that the early stages of obesity were sufficient to induce distinct differences in the ECM composition of mammary fat pads that promote TNBC cell invasion. ECM proteins previously implicated in driving TNBC invasion Collagen IV and Collagen VI, were enriched with weight gain. Together these data implicate ECM changes in the primary tumor microenvironment as mechanisms by which age and obesity contribute to breast cancer progression.
2024-06-06 | PXD050250 | Pride
Project description:Cellular extracellular matrix (ECM) and spatial heterogeneity of tumor microenvironments (TME) regulate disease progression and treatment efficacy. Developing in vitro models that recapitulate the TME promises to accelerate studies of tumor biology and identify new targets for therapy. Here, we employed extrusion-based, multi-nozzle three-dimensional (3D) bioprinting to spatially pattern triple-negative MDA-MB-231 breast cancer cells, endothelial cells, and human mammary cancer-associated fibroblasts with biomimetic ECM inks. Bioprinted models captured key features of the spatial architecture of human breast tumors, including varying-sized dense regions of cancer cells and surrounding microvessel-rich stroma. Angiogenesis and ECM stiffening occurred in the stromal area but not the cancer cell rich regions, mimicking pathological changes in patient samples. Transcriptomic analyses revealed upregulation of angiogenesis-related and ECM remodeling-related signatures in the stroma region and identified potential ligand-receptor mediators of these processes. Breast cancer cells in distinct parts of the bioprinted TME showed differing sensitivities to chemotherapy, highlighting environmentally mediated drug resistance. In summary, our 3D bioprinted tumor model will act as a platform to discover integrated functions of the TME in cancer biology and therapy.
2024-06-13 | GSE269415 | GEO
Project description:Tumor associated fibroblasts are known to play an important role in angiogenesis, however the specific signaling pathways playing an important role in this cross talk remain ill defined. Here, we studied how Ets2 transcrpiton factor signaling in tumor associated fibroblasts effected gene expression in surrounding endothelial cells in the MMTV-PyMT mammary tumor model. Inactivation of Ets2 specifically in fibroblasts using Fsp-cre significantly reduced tumor associated angiogenesis, and was indicated to effect ECM remodeling, cell adhesion and cell chemotaxis processes in neighboring endothelial cells. We have identified Ets2 in fibroblasts as a key signaling molecule to induce tumor associated angiogenesis. Additionally, this function does not rely on the presence of tumor cells, indicating a memory in fibroblasts to induce angiogenesis. Primary mammary endothelial cells were isolated from mice with or without fibroblast Ets2 in the presence of the PyMT oncogene through sorting with a CD31 antibody. RNA was extracted and samples were submitted for Affymetrix gene expression arrays
2013-12-01 | E-GEOD-44118 | biostudies-arrayexpress