DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE242830 | GEO | 2023/11/20
REPOSITORIES: GEO
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Project description:DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression
| PRJNA1014931 | ENA
Project description:In this phase I first-in-humans-study a vaccine consisting of arginase-1 (ARG1) peptides and the adjuvant Montanide ISA-51 will be tested in ten patients with metastatic solid tumors. Patients will be treated with an ARG1 vaccine every third week for 45 weeks.
| 2285526 | ecrin-mdr-crc
Project description:Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors.
2016-12-31 | GSE77208 | GEO
Project description:Deficiency of arginase is associated with hyperargininemia, and unlike the other disorders of the urea cycle, the major mechanism of metabolism of nitrogen in terrestrial mammals, are characteristic and prominent features that include spastic diplegia/tetraplegia, clonus, and hyperreflexia; loss of ambulation, intellectual disability and progressive neurological decline are other signs. To gain greater insight into the unique neuromotor features, we performed gene expression profiling of the motor cortex of a well-characterized murine model of the disorder. Co-expression network analysis suggested an abnormality with myelination, which was supported by limited existing human data. Utilizing electron microscopy, marked dysmyelination was detected in 2-week-old homozygous ARG1 knockout mice. The corticospinal tract was found to be adversely affected, supporting dysmyelination as the cause of the unique neuromuscular features and implicating oligodendrocyte impairment in a deficiency of hepatic ARG1. Following neonatal hepatic gene therapy to express ARG1, the subcortical white matter, pyramidal tract, and corticospinal tract all showed a remarkable recovery in terms of myelinated axon density and ultrastructural integrity with active wrapping of axons by nearby oligodendrocyte processes. These findings support the following conclusions: first, arginase deficiency is a leukodystrophy affecting the brain and spinal cord while sparing the peripheral nervous system; and second, neonatal AAV hepatic gene therapy can rescue the defects associated with myelinated axons, strongly implicating the functional recovery of oligodendrocytes after restoration of hepatic arginase activity. These findings support the consideration of early restoration of hepatic arginase activity in those afflicted with arginase deficiency.
2019-06-01 | GSE132058 | GEO
Project description:As sufficient extracellular arginine is crucial for T cell function, depletion of extracellular arginine by elevated Arginase 1 (Arg1) activity has emerged as a hallmark immunosuppressive mechanism. However, the potential cell-autonomous roles of arginases in T cells have remained unexplored. Here we show that the arginase isoform expressed by T cells, the mitochondrial Arginase 2 (Arg2), is a cell-intrinsic regulator of CD8+ T cell activity. Both germ-line Arg2 deletion and adoptive transfer of Arg2-/- CD8+ T cells significantly reduced tumor growth in preclinical cancer models by enhancing CD8+ T cell activation, effector function and persistence. Transcriptomic, proteomic and high-dimensional flow cytometry characterization revealed a CD8+ T cell-intrinsic role of Arg2 in modulating T cell activation, anti-tumor cytoxicity and memory formation, independently of extracellular arginine availability. Furthermore, specific deletion of Arg2 in CD8+ T cells strongly synergized with PD-1 blockade for the control of tumor growth and animal survival. These observations coupled with the finding that pharmacologic arginase inhibition accelerates activation of ex vivo human T cells unveil Arg2 as a new therapeutic target for T cell-based cancer therapies.
2019-11-02 | GSE139811 | GEO
Project description:Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. Patients with inflammatory bowel disease (IBD) show an enhanced expression and activity of Arg1 in the intestinal (sub-)mucosa, but the function of Arg1 in IBD remains poorly characterized. Here, we found that Arg1 expression correlates with the degree of inflammation in colitic tissues of IBD patients. In mice with - experimental colitis Arg1 was upregulated in an IL-4-/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre+/-Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing littermates. This correlated with decreased vessel density, compositional changes in the intestinal microbiota, diminished infiltration by myeloid cellsand an accumulation of intraluminal polyamines that are associated with epithelial healing. Dietary L-arginine restriction abolished the protective effect of Arg1-deletion, suggesting that protection is related to an increased availability of L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wildtype recipients restored the protective, anti-inflammatory phenotype while transfers from wildtype littermates into Arg1-deficient mice prevented the accelerated recovery from colitis. Thus, altered intestinal microbiota and metabolic products in Tie2-Cre+/-Arg1fl/fl mice account for the accelerated resolution from colitis in the absence of Arg1. Subsequently, L-arginine serves as novel therapeutic and diagnostic target for clinical intervention in IBD patients.
2020-06-07 | GSE151931 | GEO
Project description:Genetically engineered mouse models of lung cancer have demonstrated an important role in understanding the function of novel lung cancer oncogenes and tumor suppressor genes identified in genomic studies of human lung cancer. Further, these models are important platforms for pre-clinical therapeutic studies. Here, we generated a mouse model of lung adenocarcinoma driven by mutation of the Discoidin Domain Receptor 2 (DDR2) gene combined with loss of TP53. DDR2L63V;TP53L/L mice developed poorly differentiated lung adenocarcinomas in all transgenic animals analyzed with a latency of 40-50 weeks and a median survival of 67.5 weeks. Mice expressing wild-type DDR2 with combined TP53 loss did not form lung cancers. DDR2L63V; TP53L/L tumors displayed robust expression of DDR2 and immunohistochemical markers of lung adenocarcinoma comparable to previously generated models of lung adenocarcinoma though also displayed concomitant expression of the squamous cell markers p63 and SOX2. Tumor-derived cell lines were not solely DDR2 dependent and displayed up-regulation of and partial dependence on MYCN. Combined treatment with the BET inhibitor JQ1 and the mutltitargeted DDR2 inhibitor dasatinib inhibited tumor growth in vitro and in vivo. Together, these results suggest that DDR2 mutation can drive lung cancer initiation in vivo and provide a novel mouse model for lung cancer therapeutics studies. We used microarrays to detail the gene expression profile of mouse primary lung tumor cell lines driven by DDR2L63V;p53L/L and KrasG12D;p53L/L. When DDR2L63V; p53 and KrasG12D;p53L/L mice developed lung tumors confirmed by MRI, the mice were sacrificed and lung tumor nodules were harvested, finely minced, and cultured in 100 mm dishes with RPMI 1640/10% FBS/1% pen-strep/2mM L-Glutamine. After 3 passages, frozen stocks of these short-term cultures were prepared, and further characterized by genotyping. DDR2 expression was induced by treating cells with 2 ug/ml DOX every 2 to 3 days and confirmed by western blot analysis. The cells were cultured in RPMI 1640/10% FBS/1% pen-strep/2mM L-Glutamine. All cells were cultured at 37oC in a humidified incubator with 5% CO2.
2015-01-14 | E-GEOD-64907 | biostudies-arrayexpress
Project description:Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In 70% of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism.
2023-05-02 | PXD028292 | Pride
Project description:Genetically engineered mouse models of lung cancer have demonstrated an important role in understanding the function of novel lung cancer oncogenes and tumor suppressor genes identified in genomic studies of human lung cancer. Further, these models are important platforms for pre-clinical therapeutic studies. Here, we generated a mouse model of lung adenocarcinoma driven by mutation of the Discoidin Domain Receptor 2 (DDR2) gene combined with loss of TP53. DDR2L63V;TP53L/L mice developed poorly differentiated lung adenocarcinomas in all transgenic animals analyzed with a latency of 40-50 weeks and a median survival of 67.5 weeks. Mice expressing wild-type DDR2 with combined TP53 loss did not form lung cancers. DDR2L63V; TP53L/L tumors displayed robust expression of DDR2 and immunohistochemical markers of lung adenocarcinoma comparable to previously generated models of lung adenocarcinoma though also displayed concomitant expression of the squamous cell markers p63 and SOX2. Tumor-derived cell lines were not solely DDR2 dependent and displayed up-regulation of and partial dependence on MYCN. Combined treatment with the BET inhibitor JQ1 and the mutltitargeted DDR2 inhibitor dasatinib inhibited tumor growth in vitro and in vivo. Together, these results suggest that DDR2 mutation can drive lung cancer initiation in vivo and provide a novel mouse model for lung cancer therapeutics studies. We used microarrays to detail the gene expression profile of mouse primary lung tumor cell lines driven by DDR2L63V;p53L/L and KrasG12D;p53L/L.
2015-01-14 | GSE64907 | GEO
Project description:Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.
2023-08-14 | GSE214241 | GEO