Current Projects in the Leedham Group

Clonality and clonal ordering

We have developed techniques for examining the mutation burden of single intestinal crypts from archival paraffin embedded tissue. We use individual crypt mutation burden to analyse clonal evolution and construct tumor phylogeny by examining the spatial distribution of shared mutations in different phenotypic regions across single lesions; a technique that has been termed clonal ordering or genetic dependency analysis

'Just-right' Wnt signal levels and regional intestinal tumour formation

Mutations in the tumour suppressor gene APC result in increased canonical Wnt signaling in intestinal stem cells and are found in up to 85% of colorectal tumours. The 'just-right' hypothesis predicts that an optimal but not excessive level of Wnt signal in necessary for tumourigenesis and it is this that determines the APC mutation spectra. The optimal level of Wnt signal varies throughout the intestinal tract. We are investigating the underlying basal Wnt gradient in the human and mouse and have used transgenic mouse models to examine the effect of pan-intestinal Wnt perturbation.

Mesenchymal control of intestinal stem cells

There is increasing evidence to suggest that the epithelial stroma significantly influences tumour development and progression. BMP pathway constituents are mesenchymally expressed and act in a paracrine fashion upon the intestinal epithelium, antagonising wnt signaling and promoting differentiation in mature enterocytes. We are examining the epigenetic and transcriptional control of BMP pathway constituents and functionally characterizing the role of this pathway in intestinal stem cell control in vitro using colorectal cancer and myofibroblast cell lines and in vivo by developing transgenic animal models.