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University of Bedfordshire
Park Square
Luton
Bedfordshire
UK, LU1 3JU
BSc (Joint Hons), ARCS, DIC, PhD
Senior Lecturer in Biomedical Science at the University of Bedfordshire
Honorary Visiting Lecturer at Imperial College London
I studied chemistry and biochemistry at Imperial College, London (1990-1993) and then carried out a PhD in genetics at St. Mary’s Hospital Medical School, London and the MRC Mouse Genome Centre, Harwell (1993-1997). My PhD research, carried out in the laboratory of Professor Steve Brown, was focussed on the genetic causes of hereditary deafness in murine models.
I did my postdoctoral training in cancer genomics and cell biology at the Imperial Cancer Research Fund, Edinburgh (1997-2000) and the University of Edinburgh (2000-2003). During this time I identified the WWOX gene as a novel tumour suppressor in ovarian cancer.
In late 2003 I was appointed Lecturer in Oncology at Imperial College London, heading the Cancer Cell Genetics group. Whilst here I developed my research into the WWOX tumour suppressor gene, characterising its function in ovarian cancer. I was also a founding member of the ovarian cancer action Research Centre (Director, Professor Hani Gabra) at the Hammersmith Hospital.
In September 2010, I was appointed Senior Lecturer in Biomedical Science within the Division of Science at the University of Bedfordshire. I am also an Honorary Visiting Lecturer at Imperial College London.
My major research interests involve the role of common fragile site-associated genes in tumour development and chemoresponse, and in particular the function of the WWOX tumour suppressor.
Specific locations within our DNA (known as common fragile sites) are particularly vulnerable to damage from cancer-causing chemicals and ultra-violet light. Damage at these sites happens frequently in many different types of cancers.
Several common fragile sites contain genes that have roles in protecting us from cancer development (tumour suppressor genes), and when the fragile site becomes damaged these genes no longer function.
Understanding why these regions of DNA are sensitive to damage, and how the associated genes prevent tumours from forming, or control how well a cancer responds to chemotherapy, could help us to develop improved treatments or prevent the onset of drug resistance in patients.
Common fragile sites are regions within our chromosomes that are particularly sensitive to damage from various types of stress that affect DNA replication. Common fragile sites are found in the DNA of all individuals, but what function they have on our cells is unknown.
Common fragile sites play an important role in the development of cancer, and tumours often display deletions, rearrangements and translocations at these sites. Many common fragile sites contain genes, and the expression of these frequently becomes disrupted during tumorigenesis.
In particular, fragile site genes such as WWOX, FHIT and Parkin have been shown to be tumour suppressors, with important roles in cell proliferation, apoptosis and chemoresponse.
My research identified the fragile site gene WWOX as an ovarian cancer tumour suppressor, through a genome-wide screen for regions of tumour-associated homozygous loss (Paige 2000, Paige 2001). This gene encodes the WWOX (WW-domain containing oxidoreductase) protein, and spans the FRA16D common fragile site. My research group demonstrated homozygous deletions, aberrant splicing and complex genomic rearrangements of WWOX in ovarian cancer (Paige 2001, Alsop 2008). Furthermore, we showed that WWOX is down-regulated in 87% ovarian cancer cases (Gourley, Paige 2005). We have also investigated the influence of naturally-occurring SNP variation within the WWOX gene on ovarian cancer development (Paige 2010) and bone metabolism (manuscript submitted) in humans.
Our functional characterisation of WWOX has revealed several biological roles in ovarian cancer cells. Transfection of WWOX into a null ovarian cancer cell line abolished its tumorigenicity in nude mice, but did not affect cell proliferation or apoptosis in-vitro (Gourley, Paige 2009).
Instead, WWOX reduced membranous integrin levels, decreasing cell adhesion to fibronectin, and this likely provides the mechanism for WWOX tumour suppression.
Recently, we demonstrated that WWOX can also modulate apoptosis following treatment with specific chemotherapy drugs, though not in untreated cells, suggesting that the apoptotic role of WWOX is specific to certain stress stimuli (unpublished data).
The mechanism for this appears to be modulated via the endoplasmic reticulum stress pathway.
This research has been funded by Cancer Research UK, Scottish Hospitals Endowment Research Trust, Ovarian Cancer Action, Astra Zeneca, and private donations.
