Professor Alan Clarke
Director of Research / Director of the European Cancer Stem Cell Research Institute / Director of the Cancer Research UK Cardiff Centre
January 2016 - it is with great sadness that we learnt of the untimely death of Professor Alan Clarke.
My group uses genetically engineered murine models of cancer to model human cancer. Our principal interest is in studying colon cancer, but we also have current projects in mammary and prostate tumorigenesis. The primary aims of the group is to genetically recapitulate the different stages of cancer induction and progression, and in so doing identify and validate novel therapeutic targets for these diseases.
The principal interest of my laboratory lies in understanding the molecular basis of cancer, with a specific focus on genes involved in the very early stages of divergence from normality. The genes that control these key early events are often regarded as gatekeepers to the disease process and represent new potential targets for therapeutic intervention.
The approach we have adopted relies heavily upon the use of transgenic models, as we believe that, despite the many advantages and uses of in vitro experimentation, gene function can only be truly understood in an in vivo context. Although we make great use of existing models, we are also aware of considerable difficulties in their use and a parallel goal has therefore been to enhance and refine these systems using Cre-lox technology to render targeted genes conditional (switchable).
The primary focus of the laboratory is upon colorectal cancer, although we also have a strong interest in similar genotype –phenotype relationships in the mammary gland. In the intestine, we are investigating the mechanisms by which intestinal epithelial cells regulate normal homeostasis and through which they progress to neoplasia. Although the crypt/villus axis of the small intestine is well characterized in terms of its cell biology, the precise biological mechanisms which govern the physiology of the normal and diseased epithelium remain unclear. To investigate this fundamental relationship within the normal and diseased intestine, we have previously used a series of direct in vivo approaches using gene targeted murine strains (eg Sansom et al 2004).
These experiments have begun to reveal genetic hierarchies within the intestine, relating to elements of the Wnt, PI3-kinase, Jak-Stat, TGF-beta?and Ras pathways. These analyses repeatedly point to deregulation of the Wnt pathway as the key mediator of neoplasia in the gut. Thus, immediately following loss of the Wnt regulator Apc, we observe a 'crypt progenitor' phenotype which mirrors early stage lesions. This phenotype is characterized by the upregulation of several candidate stem cell markers, an experimental platform we are currently trying to use in a BBSRC funded project to derive cultures enriched for intestinal stem cells. Our studies have also identified the Wnt pathway as a regulator of normal intestinal homeostasis, and indeed we have observed a requirement for the Wnt pathway in crypt repopulation following injury. Layered onto this genetic analysis, we have also begun to experimentally address the role played by epigenetics in the intestine using a series of murine strains targeted for the methyl binding domain (MBD) genes- required to interpret the methylation signals on DNA. A consistent feature of these models is their impact upon the Wnt pathway, either directly or indirectly (Sansom et al 2003).
Thus activation of K-Ras and Pten augments the phenotype of Wnt deregulation, and deletion of either Mbd2 or the related protein Kaiso represses the Wnt pathway and indeed represses tumorigenesis. Transcriptome analysis of these strains has identified many novel potential therapeutic candidates for colorectal cancer and also candidate intestinal stem cell markers, a selection of which we are currently characterizing, both in terms of their potential to modify stem cell fate and tumorigenesis.
Current grant support
- Amser Justin Time
- British Skin Foundation
- Cancer Research UK
- Cancer Research Wales
- Embassy of the Arab Republic of Egypt
- Jane Hodge Foundation
- Prostate Cancer Research Centre
- Prostate Cancer UK
- The Urology Foundation
- Wellcome Trust
- Welsh Government/HEFCW
- World Cancer Research Fund
- Worldwide Cancer Research (formerly AICR)
- Bart Cornelissen - Oxford, UK
- Douglas Winton - Cambridge, UK
- Hans Clevers - Utrecht, Netherlands
- Owen Sansom - Beatson Institute, Glasgow
- Dr Trevor Hay
- Dr Andrew Hollins
- Dr Victoria Marsh Durban
- Dr Valerie Meniel
- Dr Liliana Ordonez
- Dr Karen Reed
- Dr Boris Shorning
- Miss Elaine Taylor
- Dr Sophie Wang
- Dr Madeleine Young
- Mr Matthew Zverev