Expression profiling of stroma cells from prostate cancer co-cultures, with or without TGF-beta signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE51622 | GEO | 2014/11/12
SECONDARY ACCESSION(S): PRJNA224106
REPOSITORIES: GEO
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Project description:Prostate stroma-specific TGF-beta signaling induces morphological changes in LNCaP cells. We have previously shown that stromal TGF-beta signaling regulates prostate tumor growth. To further delineate the underlying mechanisms, we generated LNCaP cells overexpressing an HA-tagged constitutively activate TGF-beta1 ligand (LNCaP-HA-TGF-β1(a)) and control LNCaP cells (LNCaP-Ctrl), and performed in vitro co-cultures of LNCaP-HA-TGF-β1(a) and LNCaP-Ctrl cells on top of the confluent HPS-19I cells, a human prostate stromal cell line. Since LNCaP cells are defective in TGF-beta receptor I (TbetaRI / ALK-5) that is essential for mediating TGF-beta signaling, only HPS19I cells are able to respond to TGF-beta ligand in these co-cultures. This provides a unique opportunity to study how prostate stromal cell-specific TGF-beta signaling regulates PCa biology.
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Project description:Tumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. Several studies have shown that the presence of TGF-β in the tumor microenvironment contributes to the skewing of neutrophils to have a more pro-tumor phenotype. However, the direct effects of TGF-β on neutrophil signaling and migration are unclear. We sought to characterize TGF-β signaling in both primary human neutrophils and the neutrophil-like cell line HL-60 and determine whether TGF-β directly induces neutrophil migration. We found that TGF-β1 does not induce neutrophil migration in either a transwell or an underagarose migration assay. However, TGF-β1 does activate signals canonically through SMAD3 and noncanonically through ERK1/2 in neutrophils in a time and dose-dependent manner. Additionally, TGF-β1 present in the tumor-conditioned media (TCM) is responsible for SMAD3 activation. Moreover, we discovered that TCM from aggressive breast cancer cells induces neutrophils to secrete leukotriene B4 (LTB4), which is a lipid mediator important for amplifying neutrophil recruitment. However, we found that TGF-β1 alone does not induce secretion of LTB4. We next performed RNA-sequencing to evaluate the effects of TGF-β1 and TCM on the neutrophil transcriptome. We found that TGF-β1 and TCM result in changes in gene transcription in HL-60 cells, specifically of two pro-tumor genes OSM and VEGFA. Together, our findings characterize the effects of TGF-β1 on neutrophil signaling, migration, and gene expression that can be applied to understanding the changes in neutrophils that occur in the tumor microenvironment.
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Project description:Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation
The interplay between PLS (Plasmin) and TSP1 (Thrombospondin-1) in TGF-β1 (Transforming growth factor-β1)is shown using mathematical modelling and in vitro
experimentents.
This model is described in the article:
Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.
Venkatraman L, Chia SM, Narmada BC, White JK, Bhowmick SS, Forbes Dewey C Jr, So PT, Tucker-Kellogg L, Yu H.
Biophys J. 2012 Sep 5;103(5):1060-8.
Abstract:
Transforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-β1, and in this work we used a systems-level approach with mathematical modeling and in vitro experiments to study the interplay between PLS and TSP1 in TGF-β1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-β1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-β1 positive feedback loop and causes an unexpected net decrease in TGF-β1 activation. To test these predictions in vitro, we treated rat hepatocytes and hepatic stellate cells with PLS, which caused proteolytic cleavage of TSP1 and decreased activation of TGF-β1. The TGF-β1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-β1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-β1 activation: a TSP1-mediated mode of high activation and a PLS-mediated mode of low activation. This switch suggests an explanation for the unexpected effects of the plasminogen activation system on TGF-β1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-β dysregulation.
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2013-03-26 | BIOMD0000000447 | BioModels
Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity. Crucial for T helper17 (Th17) cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Examination of Stat3 binding and H3K4me and H3Ac in helper T cells.
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Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity1-4. Crucial for T helper17 (Th17) cells in vivo5,6, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification7-10. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Mouse T helper 17 cell differentiation with or without TGFB
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Project description:Calcitriol and transforming growth factors beta (TGF-β) are involved in several biological pathways such as cell proliferation, differentiation, migration and invasion. Their cellular effects could be similar or opposite depending on the genetic target, cell type and context. Despite the reported association of calcitriol deficiency and disruption of the TGF-β pathway in prostate cancer and the well-known independent effects of calcitriol and TGF-βs on cancer cells, there is limited information regarding the cellular effects of calcitriol and TGF-β in combination. In this study, we in vitro analyze the combinatory effects of calcitriol and TGF-β on cell growth and apoptosis using PC-3 and DU145 human prostate cancer cell lines. Using high-throughput microarray profiling of PC-3 cells upon independent and combinatory treatments, we identified distinct transcriptional landscapes of each intervention, with a higher effect established by the combinatorial treatment, following by TGF-β1 and later by calcitriol. A set of genes and enriched pathways converge among the treatments, mainly between the combinatory scheme and TGF-β1, but the majority were treatment-specific. Of note, CYP24A1, IGFBP3, SERPINE1, CDKN1A, NOX4 and UBE2D3 were significantly up-regulated upon the combinatorial treatment whereas CCNA1, members of the CT45A and APOBEC3 family were down-regulated. By public RNA signatures, we were able to confirm the regulation by the co-treatment over cell proliferation and cell cycle. We finally investigated the possible clinical impact of genes modulated by the combinatorial treatment using benchmark prostate cancer data. This comprehensive analysis reveals that the combinatory treatment impairs cell growth without affecting apoptosis and their combinatory actions might synergize and improved their individual effects to reprogram prostate cancer signaling.
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Project description:Physical training improves insulin sensitivity and can prevent type 2 diabetes. However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response is also a potent regulator of microRNAs (miRs). Aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation and the induction of extracellular matrix components, and identified several TGF-β1-regulated miRs. qPCR validated a potent upregulation of miR143/145 and miR181a2 by TGF-β1 in both human myoblasts and differentiating myotubes. Human skeletal muscle biopsy donors participating in a supervised 8-week endurance training intervention (n=40) were categorized as responder based on fold change ISIMats (≥ +1.1) or low responder. In skeletal muscle of low responders, TGF-β signaling and miR143/145 levels were stronger induced by training than in responders. Target-mining revealed HDACs, MYHs and insulin signaling components INSR and IRS1 as potential miR143/145 targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR143/145 targets. Elevated TGF-β signaling and miR143/145 induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: By negatively impacting cell fusion and myofiber functionality via miR143 suppressing its novel targets MYH1/4; by directly impairing insulin signaling via reduction of INSR by TGF-β and fine-tuned IRS1 suppression by miR143.
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