Abstract

Changes in epithelial organisation accompany a range of human diseases from acute and chronic inflammatory conditions, bacterial infections, parasitic colonization and cancer. Understanding how epithelia are normally maintained and how molecular changes govern cellular and tissue changes in disease is necessary to develop effective treatments and detection methods. My research aims to understand the mechanisms that govern physiology of epithelial tissues, particularly gut epithelium, in health and disease. The Adenomatous Polyposis Coli (APC) protein is a key regulator of normal epithelial architecture and physiology in the gut. APC is multifunctional protein with many binding partners that link it to signaling pathways that determine the properties and functions of epithelial cells and tissues. We use the contributions of APC to gut tissue maintenance as a paradigm for understanding the earliest changes that occur in disease progression, particularly cancer. Using high resolution imaging of whole tissue we have discovered novel architectural features of healthy and precancerous gut tissue. This includes continuous muscle-like structures that support intestinal tissue units and align with the outer muscle layer of the gut, changes in tissue shape that correlates with altered alignment of mitotic spindles specifically in stem cells, decreased cell migration, and corresponding accumulation of cells in a precancerous condition. I will discuss the implications of these changes but also their link to cell biological and biochemical consequences of the mutations that produce them.