title: CDC42 inhibition suppresses progression of incipient intestinal tumors.
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.
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Sakamori
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Shiyan
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hoffman
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Soumyashree
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Pavan
authors.initials: P
authors.lastname: Vedula
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey.
authors.forename: Guangxun
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biomedical Genetics, Center for Oral Biology, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
authors.forename: Jiang
authors.initials: J
authors.lastname: Fu
authors.affiliation: Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
authors.forename: Francesca
authors.initials: F
authors.lastname: Walker
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yi
authors.affiliation: Department of Biomedical Genetics, Center for Oral Biology, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
authors.forename: Wei
authors.initials: W
authors.lastname: Hsu
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Da-Hai
authors.initials: DH
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Alexis J
authors.initials: AJ
authors.lastname: Rodriguez
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Bonder
authors.affiliation: Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Verzi
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. ngao@andromeda.rutgers.edu.
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: D051176:beta Catenin; D020764:cdc42 GTP-Binding Protein
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