DNA methylation profile of adipocytes treated with DNMT inhibitor, guadecitabine (100nM, 3X daily).
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE111617 | GEO | 2018/03/10
REPOSITORIES: GEO
Similar Datasets
Project description:Ovarian cancer (OC) cells frequently metastasize to the omentum and adipocytes play a significant role in ovarian tumor progression. Therapeutic interventions targeting aberrant DNA methylation in ovarian tumors have shown promise in the clinic but the effects of epigenetic therapy on the tumor microenvironment are understudied. Here, we examined the effect of adipocytes on OC cell behavior in culture and impact of targeting DNA methylation in adipocytes on OC metastasis. The presence of adipocytes increased OC cell migration and invasion and proximal and direct co-culture of adipocytes .increased OC proliferation alone or after treatment with carboplatin. Treatment of adipocytes with hypomethylating agent guadecitabine decreased migration and invasion of OC cells towards adipocytes. Due to this result, we performed RNA-seq of adipocytes treated with DNMT1 inhibitor to analyze differential gene expression changes that occur in the adipocyte that may explain the above observation that hypomethylating agent treatment of adipocytes decrease migration and invasion.
2018-03-02 | GSE111305 | GEO
Project description:DNA methylation profile of adipocytes treated with DNMT inhibitor, guadecitabine (100nM, 3X daily).
| PRJNA437571 | ENA
Project description:The omentum is the most common site of ovarian cancer metastasis. Immune cell clusters called milky spots are found throughout the omentum. It is however unknown if these immune cells contribute to ovarian cancer metastasis. Here we report that omental macrophages promote the migration and colonization of ovarian cancer cells to the omentum through the secretion of chemokine ligands that interact with chemokine receptor 1 (CCR1). We found that depletion of macrophages reduces ovarian cancer colonization of the omentum. RNA-sequencing of macrophages isolated from mouse omentum and mesenteric adipose tissue revealed a specific enrichment of CCL6 chemokine ligand in omental macrophages. CCL6 and the human homolog CCL23 were both necessary and sufficient to promote ovarian cancer migration by activating ERK1/2 and PI3K pathways. Importantly, inhibition of CCR1 reduced ovarian cancer colonization. These findings demonstrate a critical mechanism of omental macrophage induced colonization by ovarian cancer cells via CCR1 signaling.
2020-07-03 | GSE153685 | GEO
Project description:GSF1243: RNA-seq data of adipocytes treated with DNMT1 inhibitor, guadecitabine (100nM), for 3 days
| PRJNA436558 | ENA
Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy. 8 female C57BL/6JTgMISIIR-TAg mice with ovarian tumors of ~500 mm3 were used. 4 vehicle-treated mice (0.5% hypermellose/0.1%Tween 80);4 drug-treated mice (30 mg/kg AZD1480 in 0.5% hypermellose/0.1%Tween 80).
2015-02-01 | E-GEOD-63092 | biostudies-arrayexpress
Project description:Guadecitabine is a second generation DNA methylation inhibitor with improved pharmacokinetics and clinical activity in relapsed/refractory AML (rrAML). Here we report genome-wide DNA methylation profiles in pre-treatment samples from 116 rrAML patients treated at therapeutic doses of guadecitabine in a phase I/II study. Response rate to guadecitabine was 22 % (16CR, 42 12CRi/CRp). There were no strong mutation or methylation predictors of response. Gene expression defined a subset of patients (~20%) that had (i) high DNMT3B and low CDKN2B, CTCF and CDA expression, (ii) enrichment for KRAS/NRAS mutations, (iii) frequent CpG island hypermethylation (iv) low LINE1 hypomethylation after treatment and (v) resistance to guadecitabine in both phase I (response rate 0 % vs 33 %, p=0.07) and phase II components of the study (response rate 5 % vs. 30 %, p=0.02). Multivariate analysis identified peripheral blood blasts and hemoglobin as predictors of response and cytogenetics, gene expression, RAS mutations and hemoglobin as predictors of survival. Thus, a subset of patients (∿ 20%) with rrAML are unlikely to benefit from single agent guadecitabine. In the remaining 80%, guadecitabine is a viable option with a median survival of ∿ 8 months and a three year survival rate of over 20%.
2019-08-06 | GSE112838 | GEO
Project description:This West Coast Metabolomics Center pilot and feasibility project was granted to Ernst Lengyel (University of Chicago). The biology of ovarian cancer (OvCa) is clearly distinct from that of most epithelial tumors, in that hematogenous metastases are rare, and ovarian tumors remain confined to the peritoneal cavity. The omentum, a large pad of fat tissue (20x13x3cm) covering the bowel, is the most common site of OvCa metastasis. It consists primarily of adipocytes, which become the principal microenvironment for the OvCa cells. The underlying hypothesis for this application is that, in the presence of adipocytes, the metabolism of OvCa cells is reprogramed and shifts towards lipid utilization, which provides energy that facilitates tumor growth and metastasis. Preliminary results suggest that primary human omental adipocytes secrete cytokines which promote the metastasis of OvCa cells to the omentum and their subsequent invasion. Once metastasis has occurred, OvCa cells induce lipolysis in omental adipocytes, and use the energy derived from these lipids to proliferate. To study the metabolic changes in the tumor microenvironment we have established a 3D organotypic culture of the human omentum using primary human cells established from patient tissue. Metabolic studies will be performed on adipocytes and OvCa cells individually, on conditioned media and on adipocytes and OvCa cells co-cultured in our 3D model, with the goal of arriving at a comprehensive analysis of primary metabolites and lipids in the tumor microenvironment. In the current investigation, untargeted analysis of primary metabolites and complex lipids were conducted on adipocytes and OvCa cells individually, on conditioned media and on adipocytes and OvCa cells co-cultured in our 3D model. Analysis of oxylipins was conducted on conditioned media. To gain better understanding of the dynamic regulation of metabolic pathways we will also perform metabolic flux analysis using labeled cells (13C-glucose, 13C-glutamine) in the 3D culture model. The primary objective of this study is to gain insight into the dynamic interactions between OvCa cells and human adipocytes with the anticipation of elucidating targets of therapeutic intervention.
2014-06-11 | ST000087 | MetabolomicsWorkbench
Project description:This West Coast Metabolomics Center pilot and feasibility project was granted to Ernst Lengyel (University of Chicago). The biology of ovarian cancer (OvCa) is clearly distinct from that of most epithelial tumors, in that hematogenous metastases are rare, and ovarian tumors remain confined to the peritoneal cavity. The omentum, a large pad of fat tissue (20x13x3cm) covering the bowel, is the most common site of OvCa metastasis. It consists primarily of adipocytes, which become the principal microenvironment for the OvCa cells. The underlying hypothesis for this application is that, in the presence of adipocytes, the metabolism of OvCa cells is reprogramed and shifts towards lipid utilization, which provides energy that facilitates tumor growth and metastasis. Preliminary results suggest that primary human omental adipocytes secrete cytokines which promote the metastasis of OvCa cells to the omentum and their subsequent invasion. Once metastasis has occurred, OvCa cells induce lipolysis in omental adipocytes, and use the energy derived from these lipids to proliferate. To study the metabolic changes in the tumor microenvironment we have established a 3D organotypic culture of the human omentum using primary human cells established from patient tissue. Metabolic studies will be performed on adipocytes and OvCa cells individually, on conditioned media and on adipocytes and OvCa cells co-cultured in our 3D model, with the goal of arriving at a comprehensive analysis of primary metabolites and lipids in the tumor microenvironment. In the current investigation, untargeted analysis of primary metabolites and complex lipids were conducted on adipocytes and OvCa cells individually, on conditioned media and on adipocytes and OvCa cells co-cultured in our 3D model. Analysis of oxylipins was conducted on conditioned media. To gain better understanding of the dynamic regulation of metabolic pathways we will also perform metabolic flux analysis using labeled cells (13C-glucose, 13C-glutamine) in the 3D culture model. The primary objective of this study is to gain insight into the dynamic interactions between OvCa cells and human adipocytes with the anticipation of elucidating targets of therapeutic intervention.
2014-06-11 | ST000089 | MetabolomicsWorkbench
Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.
2015-02-01 | GSE63092 | GEO
Project description:This phase Ib/II trial studies the side effects and best dose of guadecitabine when given together with nivolumab and to see how well they work in treating participants with colorectal cancer that does not respond to treatment and has spread to other places in the body. Drugs used in chemotherapy, such as guadecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving guadecitabine and nivolumab may work better in treating participants with colorectal cancer.
| 2276905 | ecrin-mdr-crc