TGF-β induces matrisome pathological alterations and EMT in patient-derived prostate cancer tumoroids
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE230009 | GEO | 2023/11/22
REPOSITORIES: GEO
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Project description:Aims: Transforming growth factor-β (TGF-β) signalling is thought to contribute to the remodelling of extracellular matrix (ECM) of skeletal muscle and to functional decline in patients with muscular dystrophies. We wanted to determine the role of TGF-β-induced ECM remodelling in dystrophic muscle. Methods: We experimentally induced the pathological hallmarks of severe muscular dystrophy by mechanically overloading the plantaris muscle in mice. Furthermore, we determined the role of TGF-β signalling on dystrophic tissue modulation and on muscle function by (i) overloading myostatin knockout (Mstn-/- ) mice and (ii) by additional pharmacological TGF-β inhibition via halofuginone. Results: Transcriptome analysis of overloaded muscles revealed upregulation predominantly of genes associated with ECM, inflammation and metalloproteinase activity. Histology revealed in wild-type mice signs of severe muscular dystrophy including myofibres with large variation in size and internalized myonuclei, as well as increased ECM deposition. At the same time, muscle weight had increased by 208% and muscle force by 234%. Myostatin deficiency blunted the effect of overload on muscle mass (59% increase) and force (76% increase), while having no effect on ECM deposition. Concomitant treatment with halofuginone blunted overload-induced muscle hypertrophy and muscle force increase, while reducing ECM deposition and increasing myofibre size. Conclusions: ECM remodelling is associated with an increase in muscle mass and force in overload-modelled dystrophic muscle. Lack of myostatin is not advantageous and inhibition of ECM deposition by halofuginone is disadvantageous for muscle plasticity in response to stimuli that induce dystrophic muscle.
2020-08-01 | GSE127255 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2-4 years. Injury to and/or dysfunction of alveolar epithelium are strongly implicated in IPF disease initiation, but what factors determine why fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that ZEB1-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments TGF-β-induced profibrogenic responses in underlying lung fibroblasts by paracrine signalling. Here we investigated bi-directional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA sequencing (RNA-seq) of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced EMT identified many differentially expressed genes including those involved in cell migration and extracellular matrix (ECM) regulation. We confirmed that paracrine signalling between AS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a ZEB1-tissue plasminogen activator (tPA) axis. In a reciprocal fashion, paracrine signalling from TGF-β-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially via the secreted protein, SPARC. Together these data identify that aberrant bi-directional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining pro-fibrotic signals.
2021-08-19 | PXD025821 | Pride
Project description:Background: Asthma is the most common chronic lung disease in children and young adults worldwide. Airway remodelling (including increased fibroblasts and myofibroblasts in airway walls due to chronic inflammation) differentiates asthmatic from non-asthmatic airways. The increase in airway fibroblasts and myofibroblasts occurs via epithelial to mesenchymal transition (EMT) where epithelial cells lose their tight junctions and are transdifferentiated to mesenchymal cells, with further increases in myofibroblasts occurring via fibroblast-myofibroblast transition (FMT). Transforming growth factor (TGF)-β is the central EMT- and FMT-inducing cytokine. In this study, we have used next generation sequencing to delineate the changes in the fibroblast transcriptome induced by TGF-β treatment in both the short term and after differentiation into myofibroblasts, to gain an understanding of the contribution of TGF-b induced transdifferentiation to the asthmatic phenotype. The data obtained from RNAseq analysis was confirmed by quantitative PCR (qPCR). Results: As expected, we found that genes coding for intermediates in the TGF-β signalling pathways (SMADs) were differentially expressed after treatment, and genes involved in cytoskeletal pathways (FN1, LAMA, ITGB1) were differentially expressed in myofibroblasts compared to fibroblasts. Importantly, genes that were previously shown to be changed in asthmatic lungs (ADAMTS1, DSP, TIMPs, MMPs) were differentially expressed in myofibroblasts, strongly suggesting that TGF-β mediated differentiation of fibroblasts to myofibroblasts may underlie important changes in the asthmatic airway. We also identified new signalling pathways (AKT, PTEN) that are changed in myofibroblasts compared to fibroblasts. Conclusion: We have found a significant number of genes that are altered after differentiation of fibroblasts into myofibroblasts by TGF-β treatment, many of which were expected or predicted. However, we also identified novel genes and pathways that were affected after treatment of fibroblasts with TGF-β, which suggests additional pathways that that are activated during the transition between fibroblasts and myofibroblasts, and may contribute to the asthma phenotype.
2020-01-28 | GSE110021 | GEO
Project description:Our group is interested in epithelial-to-mesenchymal transition (EMT), in particular, TGF-beta induced EMT. TGF-beta signalling has been shown to be an important factor in the induction of EMT and it has been demonstrated that adding TGF-beta to epithelial cells in culture is a convenient way to study the process of EMT. In response to TGF-beta, Smad2 and 3 are activated, and form complexes with Smad4, which then regulate transcription of target genes through interactions with other DNA binding transcription factors. In the induction of EMT, the activated Smads mediate transcriptional regulation through three families of transcription factors, resulting in repression of epithelial marker gene expression and activation of mesenchymal gene expression (Xu J, et al. 2009) <br></br> Also investigated in this study is the role of H2A.Z in EMT. H2A.Z is an evolutionary conserved and a metazoan essential histone variant of the H2A class. Mice deficient in H2A.Z die during early development but the reason for this is unknown (Faast et al. 2001). Previously, our laboratory showed that the loss of H2A.Z in Xenpous laevis impaired cell movement required for the formation of the mesoderm and neural crest (Ridgway et al. 2004). Given that mesoderm formation is critically dependent upon EMT, we therefore wondered whether H2A.Z might be a chromatin regulator of EMT. We transfected MDCK cells with a lentiviral vector to express a construct encoding an shRNA targeting canine H2A.Z as we wanted to test the hypothesis that H2A.Z is involved in the maintenance of cellular identity and that its loss might trigger de-differentiation. <br></br> In order to investigate changes in histone variant H2A.Z occupancy associated with TGF-beta induced epithelial-to-mesenchymal transition (EMT) we performed H2A.Z ChIP-Seq in untreated and TGFb-treated MDCK cells. The MDCK cell line has been extensively used as a model system for EMT because they convert fully from the epithelial to the mesenchymal state in response to TGF-beta. <br></br>Please note that RNA-seq data generated in conjunction to this ChIP-seq data set were also deposited at ArrayExpress under accession number E-MTAB-5628 ( https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5628 ).
2017-10-23 | E-MTAB-5637 | biostudies-arrayexpress
Project description:NMuMG is an epithelial cell line that can be induced into EMT by TGF-β treatment or MET by TGF-β withdrawl. During EMT, several marker genes were downregulated/upregulated, which is consistent with its mesenchymal phenotype. Transcription factors that are regulated during EMT and its reverse process MET are candidate genes for the regulations of the EMT marker genes. NMuMG cells treated with vehicle, TGF-β for 11 days, or 11days of TGF-β treatment followed by TGF-β withdrawl for another 13 days. RNA from these 3 conditions of NMuMG were extracted and subject to microarray analysis
2013-07-26 | E-GEOD-48204 | biostudies-arrayexpress
Project description:RATIONALE: Measuring levels of transforming growth factor-beta (TGF-beta) in the blood of patients with epithelial cancers (head and neck, lung, breast, colorectal, and prostate) may help doctors predict how patients will respond to treatment with radiation therapy.
PURPOSE: This research study is measuring levels of TGF-beta in patients with epithelial cancers who are undergoing radiation therapy.
| 2072028 | ecrin-mdr-crc
Project description:TGF-β plays an important part in the Epithelial to Mesenchymal Transition (EMT) in many malignancies. TGF-β may have pro- and anti-tumour effects in cancer cells, depending on the context and microenvironment. On the other hand, epigenetic alterations are becoming increasingly significant in a variety of biological activities. Aberrations in epigenetic processes can cause gene function to be disrupted, as well as malignant cellular change. Understanding the role of H3K9me3 in cancer survival is becoming increasingly popular. A worldwide drop in the heterochromatin mark H3 Lys9 dimethylation (H3K9me2), an increase in the euchromatin mark H3 Lys4 trimethylation (H3K9me3), and an increase in the transcriptional mark H3 Lys36 trimethylation were discovered during TGF-β induced EMT (H3K36me3). Our study focuses on locating globally H3K9me3 related regions in response to TGF-β since TGF-β and H3K9me3 play an essential role in carcinogenesis. To further understand the role and process of H3K9me3 alteration in TGF-β induced EMT, ChIP-Sequencing was done in PC-3 prostate cancer cells.
2022-08-10 | GSE191096 | GEO
Project description:Our group is interested in epithelial-to-mesenchymal transition (EMT), in particular, TGF-beta induced EMT. TGF-beta signalling has been shown to be an important factor in the induction of EMT and it has been demonstrated that adding TGF-beta to epithelial cells in culture is a convenient way to study the process of EMT. âIn response to TGF-beta, Smad2 and 3 are activated, and form complexes with Smad4, which then regulate transcription of target genes through interactions with other DNA binding transcription factors. In the induction of EMT, the activated Smads mediate transcriptional regulation through three families of transcription factors, resulting in repression of epithelial marker gene expression and activation of mesenchymal gene expressionâ (Xu J, et al. 2009) <br></br> Also investigated in this study is the role of H2A.Z in EMT. H2A.Z is an evolutionary conserved and a metazoan essential histone variant of the H2A class. Mice deficient in H2A.Z die during early development but the reason for this is unknown (Faast et al. 2001). Previously, our laboratory showed that the loss of H2A.Z in Xenpous laevis impaired cell movement required for the formation of the mesoderm and neural crest (Ridgway et al. 2004). Given that mesoderm formation is critically dependent upon EMT, we therefore wondered whether H2A.Z might be a chromatin regulator of EMT. We transfected MDCK cells with a lentiviral vector to express a construct encoding an shRNA targeting canine H2A.Z as we wanted to test the hypothesis that H2A.Z is involved in the maintenance of cellular identity and that its loss might trigger de-differentiation. <br></br> In order to investigate changes in gene expression associated with TGF-beta induced epithelial-to-mesenchymal transition (EMT) we performed paired end RNA-Seq of poly-A selected mRNA in untreated and TGFb-treated MDCK cells. The MDCK cell line has been extensively used as a model system for EMT because they convert fully from the epithelial to the mesenchymal state in response to TGF-beta. Gene expression profiles were also generated from MDCK cells in which H2A.Z was knocked down using shRNA.<br></br>Please note that ChIP-seq data generated in conjunction to this RNA-seq data set were also deposited at ArrayExpress under accession number E-MTAB-5637 ( https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5637 ).
2017-10-23 | E-MTAB-5628 | biostudies-arrayexpress
Project description:Inappropriate activation of developmental pathways is a well-recognized tumor-promoting mechanism. Here we show that overexpression of the homeoprotein Six1, normally a developmentally restricted transcriptional regulator, increases Transforming Growth Factor-beta (TGF-beta) signaling in mammary carcinoma cells and induces an epithelial to mesenchymal transition (EMT) that is in part dependent on its ability to increase TGF-beta signaling. TGF-beta signaling and EMT have been implicated in metastatic dissemination of carcinoma. Using spontaneous and experimental metastasis mouse models, we demonstrate that Six1 overexpression promotes breast cancer metastasis. In addition, we show that, like its induction of EMT, Six1-induced experimental metastasis is dependent on its ability to activate TGF-beta signaling. Importantly, in human breast cancers Six1 significantly correlates with nuclear Smad3, and thus increased TGF-beta signaling. Further, breast cancer patients whose tumors overexpress Six1 have a shortened time to relapse and metastasis, and an overall decrease in survival. Finally, we show that the effects of Six1 on tumor progression likely extend beyond breast cancer, since its overexpression correlates with adverse outcomes in numerous other cancers, including brain, cervical, prostate, colon, kidney, and liver, amongst others. Our findings argue that Six1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis.
2010-08-21 | GSE23655 | GEO
Project description:Epithelial to mesenchymal transition (EMT) is an extreme example of cell plasticity, important for normal development, injury repair, and malignant progression. Widespread epigenetic reprogramming occurs during stem cell differentiation and malignant transformation, but EMT-related epigenetic reprogramming is poorly understood. Here we investigated epigenetic modifications during TGF-β-mediated EMT. While DNA methylation was unchanged during EMT, we found global reduction of the heterochromatin mark H3-lys9 dimethylation (H3K9Me2), increase of the euchromatin mark H3-lys4 trimethylation (H3K4Me3), and increase of the transcriptional mark H3-lys36 trimethylation (H3K36Me3). These changes were largely dependent on lysine-specific deaminase-1 (LSD1), and LSD1 loss-of-function experiments showed marked effects on EMT-driven cell migration and chemoresistance. Genome-scale mapping revealed that chromatin changes were largely specific to large organized heterochromatin K9-modifications (LOCKs), suggesting that EMT is characterized by reprogramming of specific chromatin domains across the genome. Chromatin immunoprecipitation (ChIP) was performed with antibodies against H3K9Me2 (Abcam, ab1220), H3K36Me3 (ab9050), and H3K4Me3 (ab8580) on native (unfixed) chromatin isolated from fully differentiated mouse AML12 cells (confluent, serum starved for 48hrs) either treated with TGF-β for 36hrs to induce EMT or not treated with TGF-β (0hrs, differentiated AML12 cells). DNA purified from these samples was then either whole-genome amplified (H3K36Me3 and H3K4Me3) and hybridized or directly (H3K9Me2) hybridized to NimbleGen 2.1M economy whole-genome tiling arrays #2 (listed below as array 1) and #3 (listed below as array 2), which cover mouse chromosomes 4-14. For each sample, the immunoprecipitated DNA (IP) and the input (control) DNA were hybridized to the arrays, and the IP is normalized to the input. There are 16 total samples listed below. There are 8 sample for H3K9Me2 (TGF-β and no TGF-β for arrays 1 and 2, done in replicate for a total of 8). There are 4 samples for H3K36Me3 (TGF-β and no TGF-β done on array 1 and array 2). There are 4 total samples for H3K4Me3 (TGF-β and no TGF-β done on array 1 and array 2).
2011-07-03 | E-GEOD-28291 | biostudies-arrayexpress