TAZ facilitates breast tumor growth by promoting an immune-suppressive tumor microenvironment [in-vivo and in-vitro]
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ABSTRACT:
PROVIDER: PRJNA1011904 | ENA |
REPOSITORIES: ENA
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Project description:TAZ facilitates breast tumor growth by promoting an immune-suppressive tumor microenvironment
| PRJNA1011907 | ENA
Project description:TAZ facilitates breast tumor growth by promoting an immune-suppressive tumor microenvironment [in-vitro]
| PRJNA1011912 | ENA
Project description:The core Hippo pathway module consists of a tumor-suppressive kinase cascade that inhibits the transcriptional coactivators Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple-negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ-depleted cells and their controls, harboring wild-type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumor growth. TAZ depletion resulted in smaller tumors compared to the tumors generated by control cells, in line with the notion that TAZ functions as an oncogene in breast cancer. Tumors, as well as their corresponding in vitro cultured cells, were then subjected to gene expression profiling by RNA sequencing (RNA-seq). Interestingly, pathway analysis of the RNA-seq data indicated a TAZ-dependent enrichment of ‘Inflammatory Response', a pathway correlated with TAZ expression levels also in human breast cancer tumors. Specifically, the RNA-seq analysis predicted a significant depletion of regulatory T cells (Tregs) in TAZ-deficient tumors, which was experimentally validated by the staining of tumor sections and by quantitative cytometry by time of flight (CyTOF). Strikingly, the differences in tumor size were completely abolished in immune-deficient mice, demonstrating that the immune-modulatory capacity of TAZ is critical for its oncogenic activity in this setting. Cytokine array analysis of conditioned medium from cultured cells revealed that TAZ increased the abundance of a small group of cytokines, including plasminogen activator inhibitor 1 (Serpin E1; also known as PAI-1), CCN family member 4 (CCN4; also known as WISP-1) and interleukin-23 (IL-23), suggesting a potential mechanistic explanation for its in vivo immunomodulatory effect. Together, our results imply that TAZ functions in a non-cell-autonomous manner to modify the tumor immune microenvironment and dampen the anti-tumor immune response, thereby facilitating tumor growth.
2023-09-02 | GSE242177 | GEO
Project description:The core Hippo pathway module consists of a tumor-suppressive kinase cascade that inhibits the transcriptional coactivators Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple-negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ-depleted cells and their controls, harboring wild-type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumor growth. TAZ depletion resulted in smaller tumors compared to the tumors generated by control cells, in line with the notion that TAZ functions as an oncogene in breast cancer. Tumors, as well as their corresponding in vitro cultured cells, were then subjected to gene expression profiling by RNA sequencing (RNA-seq). Interestingly, pathway analysis of the RNA-seq data indicated a TAZ-dependent enrichment of ‘Inflammatory Response', a pathway correlated with TAZ expression levels also in human breast cancer tumors. Specifically, the RNA-seq analysis predicted a significant depletion of regulatory T cells (Tregs) in TAZ-deficient tumors, which was experimentally validated by the staining of tumor sections and by quantitative cytometry by time of flight (CyTOF). Strikingly, the differences in tumor size were completely abolished in immune-deficient mice, demonstrating that the immune-modulatory capacity of TAZ is critical for its oncogenic activity in this setting. Cytokine array analysis of conditioned medium from cultured cells revealed that TAZ increased the abundance of a small group of cytokines, including plasminogen activator inhibitor 1 (Serpin E1; also known as PAI-1), CCN family member 4 (CCN4; also known as WISP-1) and interleukin-23 (IL-23), suggesting a potential mechanistic explanation for its in vivo immunomodulatory effect. Together, our results imply that TAZ functions in a non-cell-autonomous manner to modify the tumor immune microenvironment and dampen the anti-tumor immune response, thereby facilitating tumor growth.
2023-09-02 | GSE242175 | GEO
Project description:The core Hippo pathway module consists of a tumour-suppressive kinase cascade that inhibits the transcriptional coactivators Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple-negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ-depleted cells and their controls, harbouring wild-type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumour growth. TAZ depletion resulted in smaller tumours compared to the tumours generated by control cells, in line with the notion that TAZ functions as an oncogene in breast cancer. Tumours, as well as their corresponding in vitro cultured cells, were then subjected to gene expression profiling by RNA sequencing (RNA-seq). Interestingly, pathway analysis of the RNA-seq data indicated a TAZ-dependent enrichment of 'Inflammatory Response', a pathway correlated with TAZ expression levels also in human breast cancer tumours. Specifically, the RNA-seq analysis predicted a significant depletion of regulatory T cells (Tregs) in TAZ-deficient tumours, which was experimentally validated by the staining of tumour sections and by quantitative cytometry by time of flight (CyTOF). Strikingly, the differences in tumour size were completely abolished in immune-deficient mice, demonstrating that the immune-modulatory capacity of TAZ is critical for its oncogenic activity in this setting. Cytokine array analysis of conditioned medium from cultured cells revealed that TAZ increased the abundance of a small group of cytokines, including plasminogen activator inhibitor 1 (Serpin E1; also known as PAI-1), CCN family member 4 (CCN4; also known as WISP-1) and interleukin-23 (IL-23), suggesting a potential mechanistic explanation for its in vivo immunomodulatory effect. Together, our results imply that TAZ functions in a non-cell-autonomous manner to modify the tumour immune microenvironment and dampen the anti-tumour immune response, thereby facilitating tumour growth.
| S-EPMC10701768 | biostudies-literature
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2023-09-02 | GSE242178 | GEO
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| PRJNA909221 | ENA
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| PRJNA673496 | ENA
Project description:Cancer-associated fibroblasts (CAFs), the principal components of tumor microenvironment, play multiple roles in breast cancer onset and progression. While their impact is widely accepted, treatment options to target CAFs in clinical practice were not yet well established. The nuclear receptor superfamily encompasses a druggable class of molecules, expressed in various stroma and parenchymal cell types, with the interesting therapeutic potential to modulate the reactive microenvironment. Having already addressed the oncosuppressive role of the nuclear Farnesoid X Receptor (FXR) in mammary epithelial cancer cells, the present study is aimed to assess the function of FXR in CAFs and evaluate whether its activation may affect their tumor-promoting features.
2018-12-31 | E-MTAB-6343 | biostudies-arrayexpress
Project description:Molecular characterization of medulloblastoma (MB) cell origin and properties is the basis for a well-defined classification system. However, limited data is available regarding the MB tumor microenvironment. Here we present a mass spectrometry-based multi-omics study of cerebrospinal fluid (CSF) from recurrent MB patients. A group of age-matched patients without a neoplastic disease was used as control cohort. Proteome profiling identified several characteristic tumor markers and revealed a strong prevalence of anti-inflammatory and tumor-promoting proteins characteristic for alternatively polarized myeloid cells in MB samples. The up-regulation of ADAMTS1, GAP43 and GPR37 indicated hypoxia in CSF of MB patients. This notion was independently supported by metabolomics, demonstrating up-regulation of tryptophan, methionine, serine and lysine, all of which have been described to be induced upon hypoxia in CSF. The beta-oxidation promoting lipid hormone 12,13-DiHOME was found strongly upregulated, potentially promoting a metabolic shift supporting drug resistance and stem cell properties of MB cells.
2020-06-01 | PXD018226 | Pride