Author
SAKAMORI, RYOTARO - Rutgers University | |
YU, SHIYAN - Rutgers University | |
ZHANG, XIAO - Rutgers University | |
HOFFMAN, ANDREW - Rutgers University | |
SUN, JIAXIN - Rutgers University | |
DAS, SOUMYASHREE - Rutgers University | |
VEDULA, PAVAN - Rutgers University | |
LI, GUANGZUN - Rutgers University | |
FU, JIANG - University Of Rochester | |
YANG, CHUNG - Rutgers University | |
YI, ZHENG - Children'S Hospital - Cincinnati, Ohio | |
HSU, WEI - University Of Rochester | |
YU, DA-HAI - Children'S Nutrition Research Center (CNRC) | |
SHEN, LANLAN - Children'S Nutrition Research Center (CNRC) | |
RODRIGUEZ, ALEXIS - Rutgers University | |
TAKETO, MAKOTO - Kyoto University | |
BONDER, EDWARD - Rutgers University | |
VERZI, MICHAEL - Rutgers University | |
GAO, NAN - Rutgers University |
Submitted to: Cancer Research
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 7/16/2014 Publication Date: 10/1/2014 Citation: Sakamori, R., Yu, S., Zhang, X., Hoffman, A., Sun, J., Das, S., Vedula, P., Li, G., Fu, J., Yang, C.S., Yi, Z., Hsu, W., Yu, D., Shen, L., Rodriguez, A.J., Taketo, M.M., Bonder, E.M., Verzi, M.P., Gao, N. 2014. CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Research. 74(19):5480-92. Interpretive Summary: Colon cancer is one of the most commonly diagnosed cancers in the U.S., and studies have shown that the intestinal tumors can be initiated by a mutation (a change in a DNA sequence) of a tumor suppressor gene called Adenomatous Polyposis Coli (APC). It is largely unknown, however, whether other modifying genes have a significant role in APC-mediated tumor progression. Therefore, this study focused on an APC interacting gene named Cdc42. Using genetic engineering approaches and mouse models, we demonstrated that Cdc42 is required for tumor cell survival and malignant progression. Through pharmacologic experiments, we provided evidences that targeted inhibition of Cdc42 reduces tumor numbers and aggressiveness. Collectively, our findings suggest that Cdc42 could be considered as a useful marker and a potential target for selective intervention of colon cancers. Moreover, it is well-established that diet strongly influences the risk of colon cancer. Our research provides important mechanistic insights on potential nutritional intervention to prevent this common disease. Technical Abstract: Mutations in the APC or Beta-catenin genes are well-established initiators of colorectal cancer, yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacologic approaches in mouse colorectal cancer and human colorectal cancer xenograft models, we show that incipient intestinal tumor cells activate CDC42, an APC-interacting small GTPase, as a crucial step in malignant progression. In the mouse, Cdc42 ablation attenuated the tumorigenicity of mutant intestinal cells carrying single APC or Beta-catenin mutations. Similarly, human colorectal cancer with relatively higher levels of CDC42 activity was particularly sensitive to CDC42 blockade. Mechanistic studies suggested that Cdc42 may be activated at different levels, including at the level of transcriptional activation of the stem cell–enriched Rho family exchange factor Arhgef4. Our results indicate that early-stage mutant intestinal epithelial cells must recruit the pleiotropic functions of Cdc42 for malignant progression, suggesting its relevance as a biomarker and therapeutic target for selective colorectal cancer intervention. |