Journal
CANCER RESEARCH
Volume 74, Issue 19, Pages 5480-5492Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-0267
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Funding
- NIH [DK085194, CA178599, DK093809, DK102934, DK088868, DK099251, CA120915S2, CA106308, DE015654]
- Charles and Johanna Busch Memorial Award [659160]
- Rutgers University Faculty Research Grant [281708]
- New Jersey Commission on Cancer Research (NJCCR) Postdoctoral Fellowship [DFHS13PPC016]
- NJCCR Doctoral Fellowship [DFHS13PPC057]
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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. (C) 2014 AACR.
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