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Cancer Res. 2014 Oct 1;74(19):5480-92. doi: 10.1158/0008-5472.CAN-14-0267. Epub 2014 Aug 11.

CDC42 inhibition suppresses progression of incipient intestinal tumors.

Author information

1
Department of Biological Sciences, Rutgers University, Newark, New Jersey.
2
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey.
3
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey.
4
Department of Biomedical Genetics, Center for Oral Biology, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
5
Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
6
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
7
Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.
8
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
9
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
10
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
11
Department of Biological Sciences, Rutgers University, Newark, New Jersey. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. ngao@andromeda.rutgers.edu.

Abstract

Mutations in the APC or β-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 β-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.

PMID:
25113996
PMCID:
PMC4184946
DOI:
10.1158/0008-5472.CAN-14-0267
[Indexed for MEDLINE]
Free PMC Article

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