The focus of the Angus-Hill lab is to understand the roles of the Tcf/Lef family of transcription factors during the switch from proliferation to differentiation in the epithelium. Specifically, our laboratory uses mouse genetics and molecular methods to study the role of the Tcf/Lef transcription factor family in colon development, homeostasis, and diseases such as colon cancer.
Loss of Tcf4 results in colon hyperplasia.
Our research has broad relevance to the study of human colorectal cancer. Colorectal cancer is difficult to model since it develops very slowly, often over 20 years in humans, and because it requires the accumulation of multiple mutations that increase the ability of the cancer to progress and metastasize. Initiating mutations in many colon cancers affect either the Apc or b-catenin genes, leading to inappropriate activation of WNT/b-catenin signaling. While much is known about the roles of b-catenin in the development of colorectal cancer, little is known about the contributions of its obligate transcriptional partners (Tcf/Lef family) in vivo. Our studies have defined the role of Tcf4 in the colon epithelium. Tcf4 loss in adult colon results in hyperplasia and Tcf4 heterozygotous mutation causes colon tumor formation in an ApcMin mouse model that normally only develops small intestinal tumors. Currently, we are focused on understanding the molecular mechanisms of Tcf/Lef function in normal epithelial cell maintenance and in tumor formation. Our model systems allow us to identify candidate cancer genes that may provide new insights into the etiology of colorectal cancer. The lab is also working to develop additional models of colon cancer that are relevant to the human disease.