Regulatory Enhancer Profiling of Mesenchymal-type Gastric Cancer Reveals Subtype-Specific Epigenomic Landscapes and Targetable Vulnerabilities
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE186521 | GEO | 2023/08/16
REPOSITORIES: GEO
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Project description:Regulatory Enhancer Profiling of Mesenchymal-type Gastric Cancer Reveals Subtype-Specific Epigenomic Landscapes and Targetable Vulnerabilities
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Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.
2023-12-08 | PXD037670 | Pride
Project description:Mathematical modeling of immune modulation by glucocorticoids
Konstantin Yakimchuk
https://doi.org/10.1016/j.biosystems.2019.104066
Abstract
The cellular and molecular mechanisms of immunomodulatory actions of glucocorticoids (GC) remain to be identified. Using our experimental findings, a mathematical model based on a system of ordinary differential equations for characterization of the regulation of anti-tumor immune activity by the both direct and indirect GC effects was generated to study the effects of GC treatment on effector CD8+ T cells, GC-generated tolerogenic dendritic cells (DC), regulatory T cells and the growth of lymphoma cells. In addition, we compared the data from in vivo and in silico experiments. The mathematical simulations indicated that treatment with GCs may suppress anti-tumor immune response in a dose-dependent manner. The model simulations were in line with earlier experimental observations of inhibitory effects of GCs on T and NK cells and DCs. The results of this study might be useful for predicting clinical outcomes in patients receiving GC therapy.
2020-01-06 | MODEL1912170005 | BioModels
Project description:Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
| S-EPMC10570306 | biostudies-literature
Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
2019-06-20 | GSE133040 | GEO
Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
2018-11-05 | GSE121719 | GEO
Project description:Glioblastomas in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA-methylation and RNA-expression data. Tumour subtype transitions are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes.
2020-02-20 | GSE145556 | GEO
Project description:Background Gastric cancer (GC) was characterized by unique DNA methylation epigenotypes (MEs). Still, MEs, including adenocarcinoma of the esophagogastric junction (AEG) and background non-neoplastic columnar mucosae (NM), are yet to be clarified. Methods We analyzed genome-wide DNA MEs of AEG, GC, and background NM using Infinium 450k beadarray, followed by quantitative pyrosequencing validation. Large-scale data of the Cancer Genome Atlas (TCGA) were additionally reviewed. Results Unsupervised two-way hierarchical clustering using Infinium data of 21 AEG, 30 GC, and 11 NM showed four DNA MEs: extremely high-ME (E-HME), high-ME (HME), low-ME (LME), and extremely low-ME (E-LME). The promoter methylation levels were validated by pyrosequencing in 146 samples. Although almost normal mucosae were clustered into E-LME, gastric or esophagogastric junction mucosae with chronic inflammatory change due to either Helicobacter pylori infection or reflux esophagitis were clustered together into LME, which suggested that the inflammation status determined DNA MEs regardless of the causes. Three cases of Barrett’s-related adenocarcinoma were all clustered into HME. Among 94 patients whose tumors can be clustered into one of four MEs, 11 patients with E-LME cancers showed significantly shorter overall survival than the other MEs, even in multivariate Cox regression estimate. TCGA data also showed enrichment of AEG in HME and a poorer prognosis of E-LME. Conclusions E-LME cases, newly confirmed in this study, would be a unique aggressive subtype not associated with the elevation of DNA methylation levels caused by inflammation. LME could be acquired via chronic inflammation independent of the causes, and AEG frequently showed HME.
2022-10-20 | GSE207846 | GEO
Project description:More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma.
| S-EPMC9975229 | biostudies-literature