Leedham group

Gremlin 1 expression
(Click to enlarge) Ectopic epithelial expression of the BMP antagonist GREM 1 causing hereditary mixed polyposis.

Our research focuses on stem cell signalling in the tissue that lines the gut, and how it may be dysregulated in cancer.  Stem cells within intestinal crypts play a key role in maintaining gut tissue, replacing cells lost from the gut wall. Cell proliferation and differentiation in the gut is critically dependent on the Wnt pathway, as well as other cell signalling systems including the bone morphogenetic protein (BMP) pathway.  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. 

By identifying key cell-signalling mechanisms controlling gastrointestinal stem cell behaviour, in normal tissue and during tumorigenesis, we hope to uncover potential targets for therapeutic intervention. We are using a variety of techniques to analyse the expression of key signalling components in gut tissue, and developing colorectal cell lines and transgenic mouse models as a means to broaden our understanding in this field.

Recently we have become interested investigating the influence of the tumour microenvironment on cancer epithelial cell behaviour.  Growing evidence implicates the intestinal stromal, a complex supporting tissue containing populations of fibroblasts, endothelial cells and infiltrating immunocytes, in carcinogenesis.  We are studying the interaction between epithelial cells and stromal fibroblasts in colorectal precursor lesions to assess whether stromal dysregulation occurs early, through paracrine cross talk with (epi)genetically mutant, but non-invasive, epithelium. Understanding the cellular and molecular processes governing stromal influence on epithelial cell biology at all stages, and in all subtypes of colorectal tumours will be vital to clinically risk stratify patients with colorectal polyps, identify novel therapeutic targets and assist in effectively harnessing the power of the endogenous immune system.

Research funders

Cancer Research UK

Medical Research Council

Chrohns and Colitis UK

Rosetrees Trust

Worldwide Cancer Research