Ontology highlight
ABSTRACT:
PROVIDER: PRJNA770873 | ENA |
REPOSITORIES: ENA
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Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Ovarian cancer cells are known to have diminished response to TGF-beta, but it remains unclear whether TGF-beta can modulate ovarian cancer cell growth in an indirect manner through cancer-associated fibroblasts (CAFs). Using transcriptome profiling analyses on TGF-beta-treated ovarian fibroblasts, we identified a TGF-beta-responsive gene signature in ovarian fibroblasts. Identifying TGF-beta-regulated genes in the ovarian microenvironment helps in understanding the role of TGF-beta in ovarian cancer progression.
2013-12-31 | GSE40266 | GEO
Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Ovarian cancer cells are known to have diminished response to TGF-beta, but it remains unclear whether TGF-beta can modulate ovarian cancer cell growth in an indirect manner through cancer-associated fibroblasts (CAFs). Using transcriptome profiling analyses on TGF-beta-treated ovarian fibroblasts, we identified a TGF-beta-responsive gene signature in ovarian fibroblasts. Identifying TGF-beta-regulated genes in the ovarian microenvironment helps in understanding the role of TGF-beta in ovarian cancer progression. The human telomerase-immortalized ovarian fibroblast line NOF151 was treated with 5ng/mL of either TGF-beta-1 or TGF-beta-2. Total RNA was isolated from control samples and TGF-beta-treated fibroblasts samples at 48 hours post-treatment, followed by cDNA synthesis, IVT and biotin labeling. Samples were then hybridized onto Affymetrix Human Genome U133 Plus 2.0 microarrays. For each treatment group, three independent samples were prepared for the microarray experiment.
2013-12-31 | E-GEOD-40266 | biostudies-arrayexpress
Project description:Microenvironment has been suggested as an important factor contributing to how the colorectal cancer cells escape therapy, but the exact mechanism leading to chemoresistance remains elusive. Here, through modeling in vitro by cocultivation of patient-derived cancer associated fibroblasts (CAFs) with cancer stem cells (CSCs), we show that CAFs-secreted TGF-β2 is a key stromal factor that coordinates with hypoxia to promote CSC stemness and resistance to chemotherapy. GLI2, a key transcription factor of Hedgehog pathway, was identified as both necessary and sufficient in this process in which TGF-β and hypoxia-inducible factor (HIF-1α) synergize to directly induce GLI2 expression. Conversely, CSC-secreted TGF-β is also important to support the growth of CAFs but instead induce death of normal fibroblasts, suggesting a reciprocal mechanism to selectively support the CAF-CSC interaction. Small molecule inhibition of both TGF-β and GLI2 effectively reversed the chemoresistance. Finally, expression of TGFB2/HIF1A/GLI2 gene signature as a functional readout of this resistance pathway defines worse clinical outcomes and predicts patients relapse. Our observations uncover a key role of TGF-β/HIF-1α/GLI2 in microenvironment-mediated chemoresistance and reveal novel biomarker and targeting strategies to identify and treat the high risk CRC patients.
2019-01-30 | GSE93254 | GEO
Project description:Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. We show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2+) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites. CdGAP depletion in HER2+ murine primary tumors mediates crosstalk with a Dlc1-RhoA pathway and is associated with a transforming growth factor-β (TGF-β)-induced EMT transcriptional signature. To further delineate the molecular mechanisms underlying the pro-migratory role of CdGAP in breast cancer cells, we searched for CdGAP interactors by performing a proteomic analysis using HEK293 cells overexpressing GFP-CdGAP. We found that CdGAP interacts with the adaptor Talin to modulate focal adhesion dynamics and integrin activation. Moreover, HER2+ breast cancer patients with high CdGAP mRNA expression combined with a high TGF-β-EMT signature are more likely to present lymph node invasion. Our results suggest CdGAP as a candidate therapeutic target for HER2+ metastatic breast cancer by inhibiting TGF-β and Integrin/Talin signaling pathways.
2023-07-14 | PXD043376 | Pride
Project description:BACKGROUND. Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor β (TGF-β) inhibitor that targets cancer associated fibroblasts (CAFs) is promising to enhance efficacy of cancer immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy. METHODS. We measure CAFs in vivo using gallium 68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) for PET/CT imaging to guide TGF-β inhibition and sensitize metastatic colorectal cancer (CRC) to immunotherapy. A total of 131 patients with metastatic CRC underwent 68Ga-FAPI and 18F-fludeoxyglucose (18F-FDG) PET/CT imaging. Fourteen patients underwent surgery after the imaging. Relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed. Mouse cohorts of metastatic CRC were treated with TGF-β receptor (TGF-βR) inhibitor combined with KN046 which blocks PD-L1 and CTLA4, followed with 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses. RESULTS. Patients with metastatic CRC demonstrated high uptakes of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. TGF-βR inhibitor enhanced tumor infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamical changes of CAFs and tumor response to combined TGF-βR inhibitor with immunotherapy. CONCLUSION. 68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to stratify and guide patients with CRC for precise TGF-β inhibition plus immunotherapy, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.
2023-12-19 | GSE247303 | GEO
Project description:The paper describes a model of antitumor vaccine therapy.
Created by COPASI 4.25 (Build 207)
This model is described in the article:
A Mathematical Model of the Enhancement of Tumor Vaccine Efficacy by Immunotherapy
Shelby Wilson and Doron Levy
Bull Math Biol. 2012 July ; 74(7)
Abstract:
TGF-β is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-β inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-β and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-β concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-β treatment, vaccine treatment, and combined anti-TGF-β vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy.
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2024-09-02 | BIOMD0000000791 | BioModels
Project description:Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulatory components in cancer. Usually in advanced malignant stages, TGF-β signaling is elevated, but global miRNA expression is suppressed. Such a gene expression signature is well illustrated in a fibrosis/mesenchymal subtype of ovarian cancer (OC) that is of poor prognosis. However, the interplay between the two pathways in the OC subtype has not yet been elucidated. nc886 is a recently identified non-coding RNA implicated in several malignancies. nc886's high expression is associated with the poor prognosis of 285 patients in an OC cohort. Herein we have found in OC that nc886 expression is induced by TGF-β and that nc886 binds to the enzyme Dicer to inhibit the processing of miRNA precursors into mature forms. By preventing the miRNA pathway, nc886 emulates TGF-β in gene expression patterns and potentiates cell adhesion, migration, invasion, and drug resistance. We report nc886 as a novel molecular link between the TGF-β and miRNA pathways.
2017-11-08 | GSE106616 | GEO
Project description:Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% NSCLC patients, with higher frequency in lung squamous carcinomas (LUSCs). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Ptennull LUSC mouse model revealed that tumors with PTEN loss were refractory to antiPD-1, highly metastatic and fibrotic, and secreted TGF-β/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Tregs). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGF-β antibody aimed to alter this immunosuppressive microenvironment led to tumor rejection and immunological memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSC by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically.
2023-06-30 | GSE233862 | GEO
Project description:Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis. To elucidate the biological and clinical relevance of DNA methylation in ovarian cancer, we conducted expression microarray analysis of 43 cell lines and 17 primary culture specimens grown in the presence or absence of DNA methyltransferase (DNMT) inhibitors. Two parameters, induction of expression and standard deviation among untreated samples, identified 378 candidate methylated genes, many relevant to TGF-beta signaling. We analyzed 43 of these genes and they all exhibited methylation. Treatment with DNMT inhibitors increased TGF-beta pathway activity. Hierarchical clustering of ovarian cancers using the 378 genes reproducibly generated a distinct gene cluster strongly correlated with TGF-beta pathway activity that discriminates patients based on age. These data suggest that accumulation of age-related epigenetic modifications leads to suppression of TGF-beta signaling and contributes to ovarian carcinogenesis. Seventeen primary cultures of ovarian cells (two pooled normal ovarian surface epithelium, two serous borderline tumors, one endometrioid and twelve serous epithelial ovarian cancers) were mock treated or treated with 5 µM 5-AzaC for 72 hours, followed by gene expression microarray analysis to enable identification of genes differentially expressed as a result of inhibition of DNA methyltransferase activity.
2010-11-17 | E-GEOD-25427 | biostudies-arrayexpress
Project description:The survival of isolated metastatic cells and expansion into macroscopic tumour has been recognized as a limiting step for metastasis formation in several cancer types yet the determinants of this process remain largely uncharacterized. In colorectal cancer (CRC), we identify a transcriptional programme in tumour-associated stromal cells, which is intimately linked to a high risk of developing recurrent disease after therapy. A large proportion of CRCs display mutational inactivation of the TGF-beta pathway but paradoxically they are characterized by high TGF-beta production. In these tumours, TGF-beta instructs a transcriptional programme in stromal cells, which confers a high risk of developing metastatic disease. We quantified the association of TGF-beta-activated fibroblasts with disease progression. To this end, we used as surrogates the gene expression programme upregulated by addition of TGF-beta to normal colon mucosa-derived fibroblasts (CCD-Co-18) in culture. CCD-Co-18 were seeded at 60% confluence and treated with TGF-β1. Gene expression profiles were measured in duplicate using HG-U133 plus 2.0. We used RMA background correction, quantile normalization and RMA summarization (Gautier et al., 2004). A TGF-β response signature was obtained by selecting genes with limma P-value < 0.05 and at least two fold up-regulation in TGF-β treated fibroblasts.
2013-01-17 | E-GEOD-39394 | biostudies-arrayexpress