Dr Richard Clarkson
My lab focuses on identifying new ways to prevent tumours from spreading around the body, a process termed metastasis which is the leading cause of cancer related deaths. Our work involves understanding the changes that occur within tumour cells that cause them to metastasise and the development of new therapeutic strategies to either prevent this from taking place, or to eliminate the cells altogether.
Academic Team Leader
Assessment Leader: BI3352 Cancer: Molecular mechanisms, diagnostics and therapeutics
Human Tissue Officer – Research.
Research Integrity Lead for the School of Biosciences
Theme lead for the Wales Cancer Research Centre
Science Director of the Wales Cancer Bank
My lab looks at how genes that have demonstrable or presumptive roles in the removal / reorganization of supernumerary cells from adult mammary tissues could play a role in breast cancer.
Traditionally we have focused on identifying gene products that control apoptosis in mouse mammary tissues and have more recently begun to ask whether these factors contribute to the aberrant regulation of tissue homeostasis which is indicative of breast cancer. To do this, we have used conditional transgenics to modify gene activity in normal and cancer cells in vitro and in vivo, and have observed the effects of these changes on mammary tumour behaviour.
We have combined cell culture and in vivo models of mammary epithelial cell apoptosis to look at global gene expression profiles (using microarrays) of regressing tissues and to determine the role of specific transcription factors in these processes (click on Publications tab for list of relevant papers). We have focused on murine post-lactational mammary involution, a period of the normal mammary gland pregnancy cycle characterized by dramatic remodeling of the tissue architecture preceded by a wave of epithelial cell destruction and clearance. We hope that by understanding the transcriptional basis of mammary tissue remodelling in a physiologically normal context, this knowledge may be applied to the study of the same pathways in diseases affecting tissue homeostasis, such as breast cancer.
Much of our current work stems from two microarray-based studies of mammary involution and epithelial apoptosis (Clarkson 2000; 2003; 2006). Thus in a global analysis of the mammary transcriptome during the pregnancy cycle we deduced from gene expression profiles that two distinct cell-death pathways were sequentially activated during involution, the first characterized by the activation of members of the TNF superfamily, a cytokine activated pathway implicated in extrinsic (death receptor mediated) apoptosis and the second associated with remodeling enzymes. We also identified a possible molecular link between these two phases of involution, involving the transition from LIF-STAT3 to OSM-STAT1 signalling in mammary epithelial cells (Tiffen, 2008).
However, in a recent study using a conditional inhibitor of caspase activity (baculovirus p35 protein) in murine mammary tissues, we provided evidence to support the proposal that apoptosis was redundant during mammary involution (Kreuzaler, 2011). Despite this, caspase dependent pathways appear to have an unexpected role in neoplastic tissues. These observations have important implications for therapeutic strategies that recruit pro-apoptotic mechanisms.
The identification of TNF-related signaling components in the mammary gland has led us to investigate the role of TNFRsf signaling in the homeostasis of normal and neoplastic mammary tissues (Piggott, 2011). Using conditional transgenics to inhibit the endogenous TNFRsf suppressor c–FLIP, we have demonstrated a hypersensitivity of tumour cells, but not normal mammary epithelial cells, to the cytotoxic effects of the TNFsf ligand TRAIL. Central to this hypersensitivity is the complete elimination of cancer stem cell activity within tumour cell populations, irrespective of the breast cancer subtype targeted or whether the tumour cells had previously undergone treatment.
We now aim to focus on the potential for this combined c-FLIP/TRAIL treatment to be used as a therapeutic strategy in the clinic, by assessing the tumour efficacy of targeting c-FLIP inhibition long-term in pre-existing tumours in vivo.
In a separate microarray study, we used conditionally active forms of two STAT transcription factors, STAT3 and STAT5 to identify the genes responsible for their known roles in mammary cell apoptosis and differentiation respectively (Clarkson, 2006). This has lead to the identification of a number of gene targets that are likely to play important roles in the maintenance of tissue homeostasis in the mammary gland, one of which, Bcl3, is the subject of ongoing studies within our lab due to its surprising role in disease progression in vivo.
We are currently using state-of-the-art molecular modeling strategies in collaboration with Andrea Brancale and Andrew Westwell of the Cardiff School of Pharmacy, to design, synthesise and characterize novel inhibitors of Bcl3 that could be used to modify disease in breast cancer models. We are also looking at the role of Bcl3-NF-kB complexes in the aetiology of disease processes. Using conditional transgenic techniques we are specifically altering the equilibrium of NF-kB subunits bound to Bcl3 in target cells to determine the role of canonical and non-canonical NF-kB pathways dependent on Bcl3 in mammary tumours.
Our models of breast cancer are also being put to use to test novel therapeutic and diagnostic agents under development through collaborative projects with researchers in the Schools of Biosciences, Chemistry and Medicine within the University of Cardiff. These include studies of natural plant extracts with tumour specific properties, and novel PET/SPECT imaging agents for the early identification of metastatic tumours in vivo.
Future work will continue to focus on demonstrating the specific roles of the gene products identified to date in the development of breast cancer, and through our collaborations we aim to develop novel therapeutic strategies that target these new pathways.
Current grant support
- Breast Cancer Campaign
- Cancer Research Wales
- Sêr Cymru - National Research Network
- Tiziana Pharmaceuticals (Bcl3i drug development)
- Sian Griffiths Memorial Fund
- Andrew Westwell, Andrea Brancale – School of Pharmacy, Cardiff University
- Ladislav Andera – Institute of Molecular Genetics, Czech Academy of Sciences
- Peter Edwards – Department of Chemistry, Cardiff University
- Stephen Paisey, Chris Marshall - Wales Research and Diagnostic Positron Emission Tomography Imaging Centre (PETIC), Medical School, Cardiff University
- Matthias Eberl – Dept Infection, Immunity and Biochemistry, Cardiff School of Medicine
- Julia Gee – School of Pharmacy, Cardiff University
- Peter Barrett-Lee - Medical Director, Velindre Cancer Centre, Cardiff
- Dr Philippa Young - Consultant Radiologist, Cardiff Breast Clinic