Kevin Haigis

Department of Pathology and Center for Cancer Research
Massachusetts General Hospital Cancer Center
Building 149, 13th Street, Room 7.148
Charlestown, MA 02129
Tel: (617) 643-0070
Fax: (617) 726-5684
Email: khaigis@partners.org
Web Page: The Haigis Lab Page

The Haigis laboratory is working to understand how the Ras family of oncoproteins regulate homeostasis in the colonic epithelium and 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. Importantly, our laboratory maintains extensive collaborations with our clinical colleagues within the Medical School, allowing us to extend our studies to primary and archival tissues from human cancer patients.

Activating mutations in K-Ras are common in human colon cancers. 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. Tumors from these mice are remarkably similar to human colon cancers at both the molecular and histologic levels. Using our model, we have found that mutant K-Ras locks colon cancer cells in a stem-like state and prevents them from differentiating. In further characterizing this model, our immediate goals are (1) to understand how activated K-Ras contributes to malignant progression in the colon, (2) to decipher the complex network of downstream signals that mediate its oncogenic phenotype, and (3) to establish whether mutation of K-Ras confers sensitivity to specific targeted therapeutics. In the end, we hope these studies will translate into the identification of novel therapies to attack cancers expressing mutant K-Ras.

We are also exploring the relationship between Ras signaling, inflammatory bowel disease (IBD), and colon cancer. These studies focus on the N-Ras oncoprotein. We have generated mice that express mutationally activated N-Ras specifically in the intestinal epithelium and have used these animals to demonstrate that N-Ras is unique among the Ras family members in its ability to regulate p53-independent apoptosis. To gain insight into N-Ras function in the context of IBD, we are taking a systems biology approach to understanding N-Ras signaling in cells induced to undergo apoptosis by inflammatory cytokines like TNFa. The ultimate goal of these studies is to provide novel insight into Ras biology, and also to identify new therapeutic targets for IBD and IBD-associated colon cancers.

References:

• Kevin M. Haigis, Krystle R. Kendall, Yufang Wang, Ann Cheung, Marcia C. Haigis, Jonathan N. Glickman, Michiko Niwa-Kawakita, Alejandro Sweet-Cordero, Judith Sebolt-Leopold, Kevin M. Shannon, Jeffrey Settleman, Marco Giovannini, and Tyler Jacks. 2008. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nature Genetics 40:600-608.

• Jeffrey W. Keller, Kevin M. Haigis, Jeffrey L. Franklin, Robert H. Whitehead, Tyler Jacks, and Robert J. Coffey. 2007. Oncogenic K-RAS subverts the anti-apoptotic role of N-RAS and alters the N-RAS:gelsolin interaction. Oncogene 26:3051-3059.

• Kevin Haigis, Julien Sage, Jon Glickman, Sarah Shafer, and Tyler Jacks. 2006. The related retinoblastoma (Rb) and p130 genes cooperate to regulate homeostasis in the intestinal epithelium. Journal of Biological Chemistry. 281:638-647.

• Kevin M. Haigis and William F. Dove. 2003. A Robertsonian translocation suppresses a somatic recombination pathway to loss of heterozygosity. Nature Genetics 33: 33-39.