Transcription profiling of oesophageal adenocarcinoma by RNA-seq
Ontology highlight
ABSTRACT: Oesophageal adenocarcinoma (OAC) is one of the ten most prevalent forms of cancer which is showing a rapid increase in incidence and yet exhibits poor survival rates. Compared to many other common cancers, the molecular changes that occur in this disease are relatively poorly understood although genomic sequencing studies have identified several genes encoding chromatin remodeling enzymes that are frequently mutated in OAC. This finding is consistent with the knowledge that one important change that occurs in cancer cells is a reprogramming of the chromatin environment which leads to subsequent changes in their transcriptional profile.
Project description:Oesophageal adenocarcinoma (OAC) is one of the ten most prevalent forms of cancer which is showing a rapid increase in incidence and yet exhibits poor survival rates. Compared to many other common cancers, the molecular changes that occur in this disease are relatively poorly understood although genomic sequencing studies have identified several genes encoding chromatin remodeling enzymes that are frequently mutated in OAC. This finding is consistent with the knowledge that one important change that occurs in cancer cells is a reprogramming of the chromatin environment which leads to subsequent changes in their transcriptional profile.
Project description:Obesity is linked to increased mortality from many cancer types, and oesophageal adenocarcinoma displays one of the strongest epidemiological associations. The aim of this study was to dissect molecular pathways linking obesity with oesophageal adenocarcinoma and to determine if obesity is linked to increased aggressiveness of this disease. Affymetrix microarrays were used to identify altered signaling pathways in an oesophageal adenocarcinoma cell line following co-culture with isolated adipocytes from viscerally obese oesophageal adenocarcinoma patients (n=6).
Project description:Obesity is linked to increased mortality from many cancer types, and oesophageal adenocarcinoma displays one of the strongest epidemiological associations. The aim of this study was to dissect molecular pathways linking obesity with oesophageal adenocarcinoma and to determine if obesity is linked to increased aggressiveness of this disease. Affymetrix microarrays were used to identify altered signaling pathways in an oesophageal adenocarcinoma cell line following co-culture with visceral adipose tissue from viscerally obese oesophageal adenocarcinoma patients (n=6).
Project description:The clinical management of locally advanced oesophageal adenocarcinoma (OAC) commonly involves neoadjuvant chemoradiotherapy (CRT), but complete pathological response to CRT only occurs in 20-30% of patients, as radioresistance remains a major clinical challenge. In this study we used an established isogenic cell line model of radioresistant OAC to detect proteomic signatures of radioresistance in order to identify novel potential molecular and cellular targets of radioresistance in OAC. Intracellular proteins obtained from radiosensitive (OE33P) and radioresistant (OE33R) cells were subjected to LC-MS/MS analysis. We identified 5785 proteins of which 251 were significantly modulated in OE33R cells, when compared to OE33P. Gene ontology and pathway analysis of the significantly modulated proteins demonstrated altered metabolism in radioresistant cells accompanied by an inhibition of apoptosis in OE33R cells. In addition, radioresistant cells were predicted to have an activation of inflammatory and angiogenic pathways when compared to the radiosensitive cells. For the first time, we performed a comprehensive proteomic profiling of our established isogenic cell line model of radioresistant OAC, providing insights into the molecular and cellular pathways which regulates radioresistance in OAC, and we provided pathway specific signatures of radioresistance that will aid further studies on the development of targeted therapies and personalised approaches to radiotherapy, with the ultimate goal of improving response to radiotherapy in cancer patients.
Project description:This SuperSeries is composed of the following subset Series: GSE36839: Expression data from OE33 oesophageal adenocarcinoma tumour cells following 24 hour co-culture with human adipose tissue explants or control M199 medium. GSE36840: Expression data from OE33 oesophageal adenocarcinoma tumour cells following 24 hour co-culture with human adipocytes or control M199 medium. Refer to individual Series
Project description:Oesophageal adenocarcinoma (OAC) is a deadly disease with poor survival statistics and few targeted therapies available. One of the most common molecular aberrations in OAC is amplification or activation of the receptor tyrosine kinase ERBB2, and ERBB2 is targeted in the clinic for this subset of patients. However, the downstream consequences of these activating events ERBB2 activation or amplification are not well understood. Here we used a combination of phosphoproteomics, open chromatin profiling and transcriptome analysis on cell line models and patient-derived datasets to interrogate the molecular pathways operating downstream from ERBB2. Integrated analysis of these data sets converge on a model where ERBB2 activity is mediated at the transcriptional level by the transcription factor AP1. AP1 in turn controls cell behaviour by acting on cohorts of genes that regulate cell migration and adhesion, features often associated with EMT. Our study therefore provides a valuable resource for the cancer cell signalling community and reveals novel molecular determinants underlying the dysregulated behaviour of OAC cells.
Project description:Selective markers are needed for earlier diagnosis, optimal staging and treatment of oesophageal adenocarcinoma. This quantitative shotgun proteomic study used patient-matched fresh frozen tissue samples of OAC, normal oesophagus and normal stomach.
Project description:Many patients with Oesophageal Adenocarcinoma (OAC) that undergo chemoradiotherapy do not benefit from treatment due to therapy resistance. We therefore investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation, to both better understand the mechanisms involved in resistance and to find potential biomarkers. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in 8 OAC cell lines, and miRNA expression profiling was performed via high throughput qPCR. miRNAs were discovered that were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to 2 or all 3 of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in-vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of 39 patients with OAC. Hsa-miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of hsa-miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p=0.0003), and altered RNA expression. Pathway analysis of effected small non-coding RNAs and corresponding mRNA targets suggest potential mechanisms of radiation resistance in OAC.
Project description:Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigated whole genome, and where possible transcriptomic and methylation data from 115 OAC patients mostly from the DOCTOR phase II clinical trial (ANZCTR-ACTRN12609000665235). We identified genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also showed that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorised patients into four immune clusters correlated with survival. The immune suppressed cluster was associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster was associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.