CDC42 inhibition suppresses progression of incipient intestinal tumors

Ryotaro Sakamori, Shiyan Yu, Xiao Zhang, Andrew Hoffman, Jiaxin Sun, Soumyashree Das, Pavan Vedula, Guangxun Li, Jiang Fu, Francesca Walker, Chung S. Yang, Zheng Yi, Wei Hsu, Da Hai Yu, Lanlan Shen, Alexis J. Rodriguez, Makoto M. Taketo, Edward M. Bonder, Michael P. Verzi, Nan Gao

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5480-5492
Number of pages13
JournalCancer Research
Volume74
Issue number19
DOIs
StatePublished - Oct 1 2014

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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