Research summary
Colorectal cancer is the second most common cause of cancer deaths in the Western World. Despite our detailed knowledge about the molecular changes that accompany the progression of this disease, still only slightly more than 50% of patients that are diagnosed with this disease survive for more than five years. An important goal of our work is the identification of early changes in gut epithelial tissue that signify malignant potential.
A unique feature of colorectal cancer is that mutations in a single gene are common to most cancers and this mutation occurs extremely early. This gene encodes a large protein called adenomatous polyposis coli (APC). Using a variety of experimental systems and techniques including cultured cells, extracts from frog eggs, Dictyostelium, chicken embryos, and isolated proteins, we have identified the APC protein as a multifunctional protein that participates in many of the normal processes that support the formation and maintenance of normal gut epithelia: migration, division, differentiation, and death.
Together these functions explain why mutations in APC lead to overall changes in the ability of the whole intestinal tissue to organise itself: cells that lack normal APC make more mistakes, they are eliminated less efficiently, and remain more proliferative. This sets the stage for additional mutations to accumulate to drive tumour progression.
We use multi-photon microscopy to understand the relationship between less complex systems and whole gut epithelium and to validate results obtained in these less complex experimental systems. This involves visualising the tissue in three dimensions so we can detect and measure small differences between tissues that differ in APC status. Defects in tissue architecture that result from mutant APC could ultimately cause mislocalisation of cells within tissue to support early tumourigenesis.
We are using intestinal epithelium as a model system to understand how changes in a single molecule that affect specific cellular processes translate into overall changes in tissue architecture that lead to the formation of tumours. Ultimately we plan to use quantitative parameters of tissue architecture and behaviour of individual cells within the tissue to (1) differentiate human polyps (early intestinal growths) that are likely to progress to tumours, and (2) describe this tissue in four dimensions using mathematical models. Such models can then be used to make predictions about the processes and molecules that are potential targets in treating and diagnosing early stages of this common human disease. This is underpinned by cell biology and biochemical experiments to link molecular, cellular and tissue biology.
