The Wnt/ß-catenin signaling pathway plays important roles in early development, stem cell renewal, and tumorigenesis. In addition, Wnt signaling is crucial in the organization and maintenance of the human intestinal epithelium. In this pathway, many different components work together to transduce an external signal into changes in gene expression within the target cell. Upon binding its receptor, the Wnt ligand ultimately results in the stabilization of cytoplasmic ß-catenin, which is then free to enter the nucleus and activate transcription through its interaction with the TCF/LEF family of transcription factors.
Somatic mutations that result in deregulated Wnt signaling are an early event in the development of colorectal cancer, which is the second leading cause of cancer death in the United States. About 80% of colorectal cancers have APC (adenomatous polyposis coli) mutation, and about 15% have ß-catenin mutation. We have identified novel molecules in the Wnt pathways, and have provided insights into how mutations cause ß-catenin accumulation that leads to cancer.
We are also interested in the crosstalk between Wnt signaling and other signaling pathways. For example, we have identified KLF4 as a novel inhibitor of ß-catenin. KLF4 is a tumor suppressor and a key factor for stem cell re-programming. We found that KLF4 controls transcription by regulating chromatin-remodeling. We are currently investigating the molecular mechanisms of KLF4 in cancers and stem cells, including cancer stem cells.
We are collaborating with clinicians in the Markey Cancer Center to study mechanism of human cancers, especially GI and lung cancers. We are collaborating with medicinal chemists to develop small molecular inhibitors for cancer prevention and treatment. Our long-term goal is to develop novel therapeutics and diagnostics for cancer and other human diseases.