Pancreatic cancer cells render metabolic reprogramming of tumor-associated macrophages through a GARP-dependent and DNA methylation-mediated mechanism
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PROVIDER: PRJNA498044 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic cancer cells render metabolic reprogramming of tumor-associated macrophages through a GARP-dependent and DNA methylation-mediated mechanism
| PRJNA505425 | ENA
Project description:Genome wide DNA methylation profiling of cancer associated macrophages. Results showed DNA methlation status in M0 and M1-like macrophages changed after coculture with pancreatic cancer cells, but not in M2-like macrophages.
2021-11-03 | GSE121656 | GEO
Project description:Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by clonal expansion of myeloid cells, notably megakaryocytes (MKs), and aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-b1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-b1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-b1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-b1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found increased expression of GARP in BM and spleen of mice undergoing PMF and tested the therapeutic potential of a monoclonal antibody that blocks TGF-b1 activation by GARP-expressing cells. GARP:TGF-b1 blockade reduced not only fibrosis, but also clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-b1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-g signals in the spleen, were lost upon CD8 T cell depletion. Our results suggest that selective blockade of TGF-b1 activation by GARP-expressing Tregs increase a CD8 T cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms.
2022-10-27 | GSE216221 | GEO
Project description:Defects of the endosomal and lysosomal systems have been increasingly linked to adult neurodegenerative diseases1,2. Deficiencies in the retrograde trafficking pathway between endosomes and the Golgi apparatus lead to forms of Alzheimer’s and Parkinson’s diseases in the case of retromer mutations, or to the rare progressive cerebello-cerebral atrophy type 2 (PCCA2) for mutations of the Golgi-associated retrograde protein (GARP) complex3. Mutations in GARP subunits lead to abnormal cellular lipid metabolism, with accumulation of sterol esters and sphingoid bases, and concomitant lysosomal dysfunction in yeast, murine, or human cells4,5. However, whether these lipid changes cause neurodegeneration and if so, which lipids are toxic, is unknown. Here, we show that GARP defects lead to global changes of cellular protein distribution, including missorting of numerous disease-linked enzymes of sphingolipid metabolism, and to the accumulation of sphingolipid intermediates in wobbler fibroblasts. Inhibiting sphingolipid synthesis in wobbler mice, a murine model of GARP deficiency with features of amyotrophic lateral sclerosis (ALS), improved wellness scores and grip strength, and increased lifespan. Our findings indicate that regulation of sphingolipids by the GARP complex is essential for neuronal health and suggest that inhibition of sphingolipid synthesis might provide a therapeutic strategy for treatment of neurodegenerative diseases due to defects in retrograde endosome-to-Golgi membrane trafficking.
2022-02-15 | PXD007981 | Pride
Project description:We performed whole genome RNA expression analysis by RNA sequencing on M0, M1-like macrophages and M2-like macrophages, respectively, comparing to those following co-culturing with human PDA tumor cells.We focused on the genes in the glucose metabolism pathway and oxidative phosphorylation pathway that were found to be methylated and downregulated in CAFs after co-culturing with PDA tumor cells in our previous experiment. We found that PDA tumor cells induce downregulation of metabolism genes selectively in M1 macrophages than in M2 macrophages.
2021-11-03 | GSE122502 | GEO
Project description:Goals and objectives of this study: to identify genes of the Treg signature induced by consitutive expression of GARP or FOXP3 in antigen-specific Th cells with potential role for stabililization & maintenance of the regulatory program. Keywords: T-cell receptor stimulation, gene-regulation, comparative gene expression profiling, cell type comparison, human, regulatory T cells, FOXP3, GARP Human alloantigen-specific Treg cells (THU) and Th cells (CD4-39), established and described recently (Ocklenburg et al.. Lab Invest.2006; 86: 724-737), were sitmulated for 3 days with cognate antigen (EBV B cells) and IL2 as described (Ocklenburg et al.. Lab Invest.2006; 86: 724-737) and analyzed using human Affymetrix U133 2.0 in monoplicate. Th cells had been transduced with a retroviral vector containing human GARP (LRRC32) or FOXP3 and an IRES-driven GFP as marker or empty GFP control, sorted for GFP+, expanded as described recently (Ocklenburg et al.. Lab Invest.2006; 86: 724-737), and characterized functially, phenotypically, and genetically as described (WO/2007/113301). Abbreviations: Treg THU d3 = alloantigen-specific Treg cells; GFP d3 = GFP-transduced alloantigen-specific Th cells (CD4-39); FoxP3 d3 = FOXP-transduced alloantigen-specific Th cells (CD4-39); Garp d3 = GARP-transduced alloantigen-specific Th cells (CD4-39); all stimulated for 3 days (=d3) with EBV B cells and IL2.
2009-04-20 | E-GEOD-13234 | biostudies-arrayexpress
Project description:Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, the majority of cancer patients fail to respond clinically. One potential reason is the accumulation of transforming growth factor-beta (TGFb) in the tumor microenvironment (TME). TGFb drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8+ T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGF1, TGFb2 and TGFb3, with its expression restricted in effector Tregs, cancer cells as well as platelets. Herein we demonstrate that GARP overexpression in human cancers correlates with unfavorable TME and poor clinical response to ICB, raising a possibility of GARP blockade to improve cancer immunotherapy. However, it is unclear if targeting GARP in the TME is feasible without affecting platelets. We report an anti-human GARP antibody (named PIIO-1) specific for its ligand-interacting domain, effectively blocking activation of latent TGFb1. PIIO-1 lacks recognition of GARP-TGF complex on platelets. Using human GARP knock-in mice, we demonstrate that PIIO-1 does not cause thrombocytopenia, and is preferentially distributed in the TME and effective for treating both GARP+ and GARP- cancers, alone or in combination with anti-PD-1 antibody. PIIO-1 treatment reduces canonical TGFb signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8+ T cell migration into the TME in a CXCR3-dependent manner. Collectively, we conclude that GARP contributes to multiple aspects of immune resistance in cancer; anti-GARP antibody PIIO-1 is an efficacious and safe strategy to overcome ICB resistance, therefore warranting clinical development.
2022-09-21 | GSE202153 | GEO
Project description:Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we developed a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identified USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition resulted in potent growth impairment in PDAC organoids, while normal pancreatic organoids were insensitive, and caused dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinated and stabilised the HIF-1a transcription factor. PDAC is characterised by a severely hypoxic microenvironment, and USP25 depletion abrogated HIF-1a transcriptional activity and impaired glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1a axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.
2022-03-01 | GSE166077 | GEO
Project description:Goals and objectives of this study: to identify genes of the Treg signature induced by consitutive expression of GARP or FOXP3 in antigen-specific Th cells with potential role for stabililization & maintenance of the regulatory program. Keywords: T-cell receptor stimulation, gene-regulation, comparative gene expression profiling, cell type comparison, human, regulatory T cells, FOXP3, GARP
2009-04-20 | GSE13234 | GEO
Project description:Multipotent mesenchymal stromal cells (MSCs) have been shown to promote tissue repair and inhibit inflammatory/autoimmune responses in preclinical and human clinical trials A major problem for MSC-based therapies is the need to expand MSCs in vitro due to the low frequency of MSCs in tissues and the large numbers of cells needed/patient (1-10 x 10^6 cells/kg). The expansion of MSCs is associated with several problems including loss of homing capacity, onset of cellular senescence, decrease in differentiation capacityand susceptibility to genomic instability and malignant transformation, limiting the utility of MSCs as a cell-based therapy. We have recently reported that murine adipose tissue-derived MSCs (mASCs) and human ASCs (hASCs) express glycoprotein A repetitions predominant (GARP)/leucine-rich repeat-containing 32 (LRRC32). GARP binds LAP/TGF-β1 to the surface of mASCs and hASCs, regulating their secretion and activation of TGF-β1 and promoting their immunomodulatory capacity. Interestingly, silencing of GARP in ASCs significantly decreased their proliferative capacity but the mechanisms remain unknown. As the proliferative capacity of MSCs is fundamental for their success in therapy, we have aimed at understanding how GARP modulates the expansion of MSC.
2019-06-05 | GSE104254 | GEO