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Regulatory T Cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis

ABSTRACT: Regulatory T Cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis

PROVIDER: PRJNA590272 | ENA |

REPOSITORIES: ENA

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Regulatory T cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis.

Project description:Regulatory T cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis.

| PRJNA528597 | ENA

Regulatory T cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis.

Project description:Regulatory T cells (Treg) are common in the tumor microenvironment in both human pancreatic cancer and in genetically engineered mouse models of the disease. Previous studies in orthotopic syngeneic models of pancreatic cancer -recapitulated in our own data- indicated that Treg depletion results CD8+ T cell-mediated tumor regression. In human patients and in mouse models, regulatory T cells accumulate during the onset of Pancreatic Intraepithelial Neoplasia (PanIN), the earliest steps of carcinogenesis. We thus generated a genetic model to investigate the role of regulatory T cells during the onset of pancreatic carcinogenesis. Unexpectedly, depletion of Tregs during early stages of carcinogenesis led to accelerated tumor progression.

2019-03-23 | GSE128707 | GEO

Regulatory T Cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis

Project description:In human patients and in mouse models, immunosuppressive regulatory T cells(Tregs)accumulate in Pancreatic Intraepithelial Neoplasia (PanIN), the precursor lesions to pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Here, using a genetically engineered mouse that allows at will depletion of Tregs during pancreatic carcinogenesis, we determined that Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumorprogression. We demonstratedthat Treg depletion resultsin changes in the fibroblast population, exemplified by loss of Smooth Muscle Actinexpression and an increase the myeloid recruiting chemokines Ccl3, Ccl6, and Ccl8. Treg depletion further resulted ina compensatoryinflux of suppressive myeloid cells, thereby preventing an anti-tumor immune response. Mechanistically, we show that themyeloid recruitment was driven through the CCR1 axis, with the receptor expressed on tumor associated myeloid cells and several ligands up-regulated in epithelial cells and fibroblasts upon Treg depletion. Finally,blockade of CCR1 signalingcombined with Treg-depletionsuccessfully inhibitedtumorigenesis, uncovering the immune-suppressive myeloid CCR1 axis as a potential therapeutic targetin pancreatic cancer.

2020-01-13 | GSE140628 | GEO

Sox4 links tumor suppression to accelerated aging in mice

Project description:Sox4 links tumor suppression to accelerated aging in mice

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Huntington disease mice exhibit a TCF7L2-responsive suppression of both homeostatic and compensatory remyelination

Project description:Huntington disease mice exhibit a TCF7L2-responsive suppression of both homeostatic and compensatory remyelination

| PRJNA751861 | ENA

Oocyte-specific deletion of Mitofusin1 causes female infertility and accelerated follicular depletion

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Epithelial XBP1 coordinates TP53-driven DNA damage responses and suppression of intestinal carcinogenesis

Project description:Epithelial XBP1 coordinates TP53-driven DNA damage responses and suppression of intestinal carcinogenesis

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Proteomic assessments of muscle tissues in cattle that are diet restricted and subsequently undergo compensatory growth

Project description:Compensatory growth is a naturally occurring accelerated growth phenomenon observed in cattle upon re-alimentation following a prior period of dietary restriction (Hornick et al., 2000). It is incorporated into man production systems as a method to reduce feed costs and consequently is economically important for animal production systems. The goal of our research project is to identify biomarkers for cattle with a superior ability to display compensatory growth. Transcriptional profiling studies of liver and muscle tissues in cattle have shown large numbers of differentially expressed genes in animals undergoing dietary restriction and subsequent compensatory growth when compared to a continuously-fed ad libitum control group of cattle (Connor et al., 2010; Keogh et al., 2016a,b). Given the identification of differential expression at the transcript level, the intended project aims to evaluate potential differences in protein abundance between animals that are diet restricted and subsequently undergo compensatory growth compared to a continuously-fed ad libitum control group of cattle. Differences in genes that are apparent at both the protein and the transcript level are more likely to be transferable across breed type (Snelling et al., 2013) and consequently have more utility for incorporation within genomic selection breeding programs for cattle evaluations.

2020-02-17 | PXD014374 | Pride

Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis

Project description:Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload evoked by FBXL5 ablation gives rise to oxidative stress, tissue damage, inflammation and compensatory proliferation in hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting effect of FBXL5 deficiency in the liver is also operative in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis induced by iron overload. Dysregulation of FBXL5-mediated cellular iron homeostasis was also found to be associated with poor prognosis in human HCC, implicating FBXL5 plays a significant role in defense against hepatocarcinogenesis.

2019-03-09 | GSE124370 | GEO

Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs

Project description:Disruption of skin homeostasis by environmental insults activates pathologic circuitries leading to inflammation and carcinogenesis. Galectin-7 (Gal-7), a lectin preferentially expressed in keratinocytes, has been implicated in wound healing and defective skin repair. Here we report using genetically-engineered mouse models and human samples, essential roles for Gal-7 during skin carcinogenesis via coordinated intracellular and extracellular mechanisms. Heightened Gal-7 expression delineated malignant lesions in non-melanoma skin cancer (NMSC) patients and shaped the course of skin carcinogenesis in mice. Intracellularly, increased Gal-7 conferred genomic instability to skin lesions and favored transcription of inflammation-related genes reprogramming the immune landscape toward a myeloid immunoregulatory profile. Extracellularly, Gal-7 accelerated skin carcinogenesis through glycan-dependent induction of monocytic myeloid-derived suppressor cells with enhanced immune regulatory activity. Our findings identify a lectin-driven molecular circuitry that promotes skin carcinogenesis by coupling genomic instability, transcriptional regulation and myeloid immunosuppressive programs, suggesting a potential therapeutic target for the treatment of NMSC.

2023-01-13 | GSE165285 | GEO

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