Professor Simon Leedham is a Wellcome Senior Research Fellow in Clinical Science and an Honorary Consultant Gastroenterologist
Outline of Research
Adult gastrointestinal stem cells are the targets of carcinogenic gene mutations and are believed to be the cells of origin of luminal gastrointestinal cancers. Our published work has examined the clonality and genetic mutation burden of pre-neoplastic gastrointestinal disease. Our current research focuses on the homeostatic cell-signaling pathways that control intestinal stem cells and the dysregulation of these pathways in carcinogenesis. The wnt pathway is the best characterised system and promotes the maintenance and proliferation of stem cells, however other signaling pathways such as the Bone Morphogenetic Protein (BMP) and Notch pathway cross-talk and interact with wnt signaling. Recent work from our laboratory on hereditary polyposis syndromes and genome-wide association studies in sporadic colorectal cancer patients has implicated the BMP pathway’s involvement in predisposition to colorectal cancer.
Projects in the lab
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.
Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.
Malla SB. et al, (2024), Nat Genet
Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.
Beach C. et al, (2023), The Journal of clinical investigation, 133
Poor diagnostic reproducibility in the identification of non-conventional dysplasia in colitis impacts the application of histological stratification tools.
Nasreddin N. et al, (2023), Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Virtual alignment of pathology image series for multi-gigapixel whole slide images.
Gatenbee CD. et al, (2023), Nature communications, 14
β-catenin drives butyrophilin-like molecule loss and γδ T-cell exclusion in colon cancer.
Suzuki T. et al, (2023), Cancer immunology research