| Angiogenesis |
Apoptosis |
Apoptosis, molecular control |
Autoimmune and hypersensitivity diseases |
| Autoimmunity |
Bioinformatics |
Breast cancer |
Cancer genetics and cell biology including metastasis |
| Cell Death |
Cell cycle control |
Cellular, molecular and developmental immunology |
Chronic Disease |
| Chronic inflamation |
Coagulation biochemistry and disorders |
Cytokines, Nitric Oxide |
Cytoskelton, cell division |
| DNA transcription and translation |
Gene targeting in breast cancer |
Gene therapy |
Gene transcription in human cancer |
| General surgery, upper GI, colorectal and breast |
Genetic/Molecular epidemiology |
Genomics |
Haemotology |
| Human genetics |
Immune System |
Immune system |
Immunoassays |
| Immunochemistry and immunogenetics |
Immunological response to surgical trauma |
Immunotherapies |
Immunotherapies for Cancer |
| Inflammation and coagulation syndromes |
Inflammatory bowel disease |
Innate immunology |
Intra and intercellular signalling |
| Leukemias and lymphomas |
Leukocyte Biology |
Mammilian and human genetics and genomics |
Membrane and protein trafficking |
| Mucosal immunology |
Oesophageal cancer |
Oesophageal, gastric, intestinal and pancreatic diseases |
Oncogenes, apoptosis and tumour development |
| Protein processing, stability and regulation |
Protein sequence, function and expression |
Quantitative and molecular genetics |
RNA processing, stability and degradation |
| Radiotherapy |
Radiotherapy, Biological response modifiers and chemoprevention |
Regulatory methods of gene expression |
Stem Cell biology and hematopoiesis |
| Therapeutic and Clinical oncology |
Therapeutic radiography |
Tumour immunology and immunotherapy |
Vascular Biology, Thrombosis |
| Project title |
The role of microRNA and random mitochondrial DNA mutations in a novel clinically-relevant isogenic model of radioresistance in oesophageal adenocarcinoma |
| Summary |
Oesophageal cancer has one of the worst prognoses for patients of all cancers, and its occurrence is increasing faster than that of any other disease in Ireland. The current treatment for this disease involves a combination of chemotherapy and radiation therapy (neo-CRT) before surgery. However, tumour resistance to radiation therapy remains a significant problem. Our group recently developed a cell model that has been found to reflect radioresistance in oesophageal adenocarcinoma patients. Our preliminary analysis of this model identified certain molecular features as contributing to the radioresistance. Importantly, a number of these differences were authenticated in patient samples, demonstrating clinical utility of the model. The aim of this study is to further explore this model by; firstly, profiling the miRNA compartment to identify those miRNA candidates likely to be involved in the radioresistant phenotype. miRNA are tiny pieces of genetic information that regulate cell function. We will assess the contributions of key miRNA by determining their effects on altering cell sensitivity to radiation, DNA damage induction and repair, DNA repair gene expression, ROS and associated antioxidant levels, which are all linked to radioresistance in our model. Secondly, given the close proximity of the mitochondrial genome to the ROS production site and the low proficiency of mitochondrial DNA repair mechanisms, we aim to examine the contribution of mitochondrial genome instability to radioresistance. This will be accomplished by assessing the levels of mitochondrial mutations using a new random assay and correlating our findings with the radioresistance. Importantly, we will assess radioresistance-associated miRNA and mitochondrial mutations in pre-treatment tumour samples from patients and compare with downstream responses to neo-CRT and survival. Understanding the mechanisms of, and identifying cellular features predictive of radioresistance for oesophageal adenocarcinoma will aid doctors selecting the right patients for neo-CRT, ultimately improving treatment efficacy and patient survival. |
| Funding Agency |
Health Research Board |
| Programme |
Health Research Award |
| Type of Project |
|
| Date from |
Oct 2011 |
| Date to |
Sept 2013 |
| Person Months |
24 |
|
|
| Project title |
Tissue and Serum microRNA signatures for predicting response to chemoradiotherapy for oesophageal adenocarcinoma |
| Summary |
Oesophageal cancer is increasing in incidence and has one of the worst prognoses of all cancers. Current therapeutic regimens tend toward neoadjuvant chemoradiotherapy (neo-CRT), for which less then 25% of patients respond. Presently, there are no reports describing miRNA signatures for predicting response to neo-CRT in oesophageal cancer. Studies to determine molecular predictors of response to chemoradiotherapy are essential to improve patient selection and therapeutic efficacy. This study aims to examine, by microarray, the differential expression of miRNA in both matched oesophageal tumour tissue and serum samples from responders and non-responders to neo-CRT. The miRNA data will be applied to a software-based predictive algorithm, establishing a miRNA signature of response. This predictive model will be used to validate the tumour and serum miRNA signature in an independent cohort of patients. Additionally, the miRNA data will be combined with existing gene expression data from a predictive signature previously generated in our lab, establishing a more refined miRNA-gene expression signature for neo-CRT responders and non-responders. Functionally, the relative contributions of specific signature miRNAs to chemo- and radio-sensitivity will be assessed using isogenic cell lines models of chemo- and radio-resistance. This will be achieved using a state-of-the-art miRNA cloning and manipulation strategy. This work has important implications for oesophageal cancer therapy, in that the identification of gene and miRNA signatures predicting patient response to treatment will provide a platform for the development of a new diagnostic test, ultimately improving patient selection, treatment benefit, and survival. |
| Funding Agency |
Irish Cancer Society |
| Programme |
Research Fellowship |
| Type of Project |
Research Fellowship |
| Date from |
Oct 2010 |
| Date to |
Sept 2013 |
| Person Months |
36 |
|
|
| Project title |
The role of the chemokine CCL28 (MEC) in oesophageal adenocarcinoma progression: interaction between the immune system and the tumour |
| Summary |
Previous work in our laboratory has identified a gene 'signature' that predicts, with a high level of accuracy, oesophageal cancer patients who will respond to pre-surgical chemoradiation therapy (CRT). Embedded within this signature are a number of genes that are immune-related. One gene, CCL28, was shown to be expressed at significantly higher levels in tumour tissue from CRT non-responders, compared with responder tumour tissue. CCL28 is a chemokine that displays chemotactic activity for CCR10-expressing T cells and CCR3-expressing eosinophils. These cells are important mediators of inflammation in oesophageal cancer. CCL28 is not normally expressed in the oesophagus, but is preferentially expressed by columnar epithelial cells, such as those found in the colon, salivary gland, mammary gland, trachea, and lung. CCL28 expression can be increased by pro-inflammatory cytokines, such as IL-1B and TNF-a, which can be induced by bile acids; this implies a role for CCL28 in effector cell recruitment to sites of refluxate-induced epithelial injury. We propose that CCL28 expression increases as normal oesophageal tissue progresses through the Barrett's metaplasia-dysplasia-adenocarcinoma sequence, which occurs through chronic exposure to refluxate. In this study, we will examine the relationship between IL-1B, TNF-a, and CCL28 expression in response to bile acids in normal, Barrett's, and oesophageal adenocarcinoma cell lines and tissue explants. Furthermore, using chemotactic assays we will examine the subpopulations of T cells and eosinophils recruited in response to CCL28. Using tissue microarrays, we will examine CCR3- and CCR10-expressing immune infiltrates and correlate these with disease status and tumour response to chemoradiation. |
| Funding Agency |
Irish Cancer Society |
| Programme |
Research Scholarship |
| Type of Project |
Cancer biology, immunology |
| Date from |
Oct 2010 |
| Date to |
Sept 2013 |
| Person Months |
36 |
|
|
| microRNA in Oncogenesis in, editor(s)Trygve Tollefsbol , Epigenetics in Human Disease, Elsevier, 2012, [Niamh Lynam-Lennon, Steven G. Gray, Stephen G. Maher] |
| Stephen G. Maher, Dermot T. McDowell, Ben C. Collins, Cian Muldoon, William M. Gallagher, John V. Reynolds, Serum proteomic profiling reveals that pre-treatment complement protein levels are predictive of esophageal cancer patient response to neo-adjuvant chemoradiation, Annals of Surgery, 254, (5), 2011 |
| Gijsbert J. Hotte, Niamh Lynam-Lennon, John V. Reynolds, Stephen G. Maher, Radiation sensitivity of oesophageal adenocarcinoma: The contribution of the RNA-binding protein RNPC1 and p21-mediated cell cycle arrest to radioresistance, Radiation Research, 2011 |
| Niamh Lynam-Lennon, Stephen G. Maher, John V. Reynolds, The Roles of microRNA in Cancer and Apoptosis, Biological Reviews, 84, (1), 2009, p55 - 71 |
| Stephen G. Maher, Charles M. Gillham, Shane P. Duggan, Paul C. Smyth, Nicola Miller, Cian Muldoon, Kenneth J. O'Byrne, Orla M. Sheils, Donal Hollywood, John V. Reynolds, Gene expression microarray analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of oesophageal cancer, Annals of Surgery, 250, (5), 2009, p729 - 737 |
| More Publications and Other Research Outputs >>> |
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Last Updated:25-APR-2014 |