Cancer Cell Genetics Group
The Cancer Cell Genetics group, led by Dr Adam Paige, is located within the Ovarian Cancer Action Research Centre at the Hammersmith Hospital. The major research interests of the group involve the role of common fragile site-associated genes in tumour development and chemoresponse, and in particular the function of the WWOX tumour suppressor.
Research
Our research in a nutshell
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.
Our 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. Our 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.
Localisation of WWOX (green) and integrin alpha3 (red) in an ovarian cancer cell line
In addition we have interests in the development and use of murine models of ovarian tumorigenicity in order to validate candidate ovarian cancer genes, and to test novel therapeutic approaches targeting these genes. In collaboration with Dr Sadaf Ghaem-Maghami (Imperial College) and Dr John Maher (King’s College London), we are utilising bioluminescent imaging of peritoneal ovarian cancer growth in Scid mouse models to explore the therapeutic potential of novel immunotherapies for ovarian cancer.
Funding
We have been supported by awards from both charitable and commercial organisations. Our research is currently funded by Ovarian Cancer Action, Astra Zeneca, the US Department of Defense and private donations.
Publications
The group's publications are available here.
