Our overarching goal is to understand the relationship between colonic epithelial differentiation and the malignant progression of colon cancer, which claims almost 60,000 lives per year in the United States. To develop next-generation therapeutics, it is critical to understand how specific mutations modulate their respective signaling pathways to affect colon cancer initiation, progression, and metastasis. Our primary approach is to genetically manipulate relevant signaling pathways both in vivo, in the mouse colonic epithelium, and in vitro, in human colorectal cancer cells. These complementary approaches are integrated through cell biology, biochemistry, and systems biology.
The main focus of the lab is to understand the oncogenic properties of K-Ras and N-Ras, both of which are commonly mutated in colorectal cancers. We have generated a mouse model of colon cancer that incorporates oncogenic K-Ras signaling and demonstrated that this oncogene accelerates tumor progression by expanding the stem cell population and by suppressing differentiation within the cancer epithelium. Currently, we are using this model to characterize the molecular signaling pathways that mediate the K-Ras phenotype. In addition, we are using these mice as a platform in which to test novel anti-cancer therapies.
We are also exploring the relationship between Ras signaling, inflammatory bowel disease, and colon cancer. In this context, we are studying mice that express activated N-Ras in their gastrointestinal tract. We have found that intestinal epithelial cells expressing activated N-Ras are resistant to a variety of pro-apoptotic stimuli, including TNFα. We are working to understand how N-Ras exerts this anti-apoptotic effect and to characterize how N-Ras mutations contribute to tumorigenesis in the context of inflammatory bowel disease.