Abstract SY07-01: The adenomatous polyposis coli protein makes multiple contributions to architecture of gut epithelial cells and tissue

Abstract

Abstract Gut epithelium can be subject to acute and chronic inflammatory conditions, bacterial infections, parasitic colonization and cancer. It is the most dynamic epithelium in the adult body and relies on cellular processes that govern all epithelial tissues. Understanding how it is normally maintained and how molecular changes create cellular and tissue changes in disease is key for developing effective treatments and detection methods. We are using changes in gut epithelium that accompany colorectal cancer as a model for understanding changes in epithelial physiology in disease. The earliest identifiable molecular change in sporadic colorectal cancer is mutation of the Adenomatous polyposis coli (APC) gene. Such mutations are usually truncation mutations and are also responsible for familial adenomatous polyposis (FAP), a familial form of colorectal cancer. Understanding how molecular changes in APC drive such cellular and tissue changes will yield important information about normal and disease-associated physiology. APC is a multifunctional protein that contributes to proliferation, differentiation, cell-cell and cell-substrate adhesion, apoptosis, and migration. APC thus represents a central node between seemingly distinct signalling networks. Many of the protein interactions that contribute to these diverse functions have been described. The first binding partner identified for APC was beta-catenin, a protein that supports adhesion proteins and activates transcription factors that drive genes characteristic of less differentiated, more proliferative cells. APC helps to target beta-catenin for proteasomal degradation. This is regulated by Wnt signalling and places APC at the core of a pathway that is crucial for the development of many tissues and organs. APC also interacts directly with cytoskeletal proteins and their regulators. These interactions contribute directly to cell migration and adhesion, but also cell division and apoptosis. Mutations in APC cause stabilisation of beta-catenin, which results in continued proliferation and decreased differentiation. In this context, the additional loss of the beta-catenin-independent functions of APC (genetic instability, decreased cell migration and decreased apoptosis) are particularly relevant because they confer a significant advantage to cells. Thus APC is a gatekeeper that ensures the fidelity of the processes that govern normal tissue maintenance in gut but also other epithelia. Work in my laboratory aims to understand the spectrum of APC functions, how they are regulated and coordinated with each other and how they contribute to overall epithelial biology. To this end we use a host of techniques that span multiple levels of resolution. This includes biochemical assays to reveal the molecular mechanisms that underpin APC interactions, high-resolution live imaging of cells and whole tissues to elucidate spatial and temporal regulation of APC protein complexes, and functional readouts to establish the contribution of APC to cell migration, differentiation, proliferation, adhesion, and cell death. One area of particular interest is contribution of APC and its associated pathways to the maintenance of stem cells in gut epithelium. Ultimately, we aim to use data on APC and its interactions to create an interaction network for APC that integrates the best available supporting evidence in a coherent model that describes the molecular basis for the contribution of APC to the normal biology of gut epithelium. We aim to integrate this with three- and four-dimensional models of tissue architecture that are informed by our detailed measurement of tissue architecture in normal and precancerous tissue. My presentation will provide an up-to-date summary of these studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY07-01. doi:10.1158/1538-7445.AM2011-SY07-01