Research Interests:
Colorectal cancer claims almost 60,000 lives per year in the United States. Despite our expansive knowledge of the molecular pathology of this disease, mortality due to colon cancer remains unaffected. To develop next-generation therapeutics, it is critical to understand how specific mutations modulate their respective signaling pathways to affect cancer initiation, progression, and metastasis. To this end, the overarching goal of our laboratory is to understand how the Ras family of oncoproteins, and their direct downstream effector pathways, promote colon cancer progression.
Our primary approach is to genetically manipulate Ras signaling pathways both in vivo, in the mouse colonic epithelium, and in vitro, in human colorectal cancer cells. These complementary experimental systems are integrated through cell biology, biochemistry, and systems biology.
Activating mutations in the K-Ras and B-Raf oncoproteins are common in human colon cancers. Regardless of the well-established connection between K-Ras and B-Raf mutations and colon cancer progression, the molecular mechanisms underlying this association are poorly characterized. We have recently developed a novel mouse model of colon cancer that relies on mutationally activated K-Ras expressed in the context of an Apc-mutant colonic tumor (Haigis et al., Submitted). As an extension of these studies, our immediate goals are (1) to understand how activated K-Ras and B-Raf contribute to malignant progression in the colon, (2) to decipher the complex network of downstream signals that mediate their oncogenic phenotypes, and (3) to establish whether mutations in these oncogenes determine sensitivity to specific therapeutics. We are addressing these issues through the use of mice genetically engineered to express mutationally activated forms of K-Ras and/or B-Raf. Our driving hypothesis is that mutant K-Ras locks Apc-mutant colon cancer cells in a stem-like state, in the process conferring resistance to therapies that would otherwise promote differentiation. A major question is whether mutant K-Ras exerts unique phenotypic effects in the presence of distinct tumor-initiating mutations, and whether this can affect the response of colonic cancers to therapy. In parallel to our studies on K-Ras, we are analyzing the phenotypic effects of activated B-Raf in the colon epithelium. Are mutations in K-Ras and B-Raf functionally equivalent or do these molecules have unique oncogenic properties?
We are also exploring the relationship between Ras signaling, inflammatory bowel disease (IBD), and colon cancer. Compared to its closely related family members K-Ras and H-Ras, the function of N-Ras is poorly understood. To dissect the function of N-Ras in vivo, we have generated mice that express mutationally activated N-Ras specifically in the intestinal epithelium. Our preliminary analyses suggest that N-Ras is unique among the Ras family members in its ability to regulate p53-independent apoptosis. We surmise that the pathways that are regulated by N-Ras may be important in certain diseases that are characterized by abnormally high rates of apoptosis, for example IBD. Inflammation-induced apoptosis of the intestinal epithelium is a hallmark of IBD and there are currently no effective treatments for this chronic and debilitating condition, which affects over 1 million Americans. We are using the inflammation-induced apoptosis that occurs during IBD as a paradigm to study N-Ras function. We predict that a thorough understanding of N-Ras function, and by extension its downstream effector pathways, will lead to the identification of novel molecular targets for more effective IBD therapies.
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