Over 90% hereditary and sporadic colorectal cancers are caused by initial mutation in the adenomatous polyposis coli (APC) gene. The subsequent tumorigenesis is fueled by increased chromosomal instability, which rapidly incorporates oncogenic mutations. Hypermutated colorectal cancers are often lethal;therefore preventing early-stage cells from becoming malignant is key to combating this disease. The spindle and chromosomal segregation defects elicited by APC mutations would, in theory, trigger the mitotic checkpoint, cell cycle arrest, and apoptotic cell death, yet a great portion of mutant cells escape the checkpoint, becoming aneuploid and polyploidy-hallmarks of colon cancers. How do the earliest precancerous cells adapt for survival? Published work in the applicant's lab has revealed that Cdc42, a small GTPase of the Rho subfamily, is critical for intestinal stem cell survival, division, and differentiation. Strong preliminary data further demonstrate that Cdc42 is activated in early APCMin/+ mouse intestinal epithelia, prior to the onset of polyposis, and dramatically activated in intestinal microadenomas in mice carrying ?-catenin-dominant active mutation. Elevated Cdc42 appears to render tumor cells capable of survival and constructing aberrant crypt-like Wnt-secreting tumor microenvironments in vivo. The objective is to tackle the mechanism of pro-survival adaptation during early colorectal tumorigenesis, and to explore Cdc42-inhibition as a means of eradicating early-stage colorectal cancers. The hypothesis is that Cdc42 critically mediates pro-survival adaptation and niche construction in APC and/or ?-catenin mutant colorectal cancer cells;and targeting Cdc42 will effectively abrogate these prevalent types of colorectal cancer in vivo.
Aim I will explore the suppressive efficacy of Cdc42 inhibition on human colorectal cancer tumorigenesis;
and Aim II will explore the efficacy of Cdc42 inhibition on the tumorigenesis of a dietary carcinogen-induced colorectal cancer mouse model. This exploratory project composed of high-risk in vivo experiments is significant because it tests the efficacy of novel Cdc42 small molecule inhibitor on the natural pathogenesis of colon cancers, which will open the door for drug discovery and improvement. This project is, in our view, innovative because it explores the concept of inducing "synthetic lethality" by a new small GTPase inhibitor in a novel mouse colon cancer model that recapitulates the natural pathogenesis of human disease counterpart. Successful completion of this project is expected to greatly elevate our basic and clinical understanding of the mechanism of adaptation in colorectal cancer cells.
|Zhang, Xiao; Gao, Nan (2016) RAB and RHO GTPases regulate intestinal crypt cell homeostasis and enterocyte function. Small GTPases 7:59-64|
|Feng, Qiang; Gao, Nan (2015) Keeping Wnt signalosome in check by vesicular traffic. J Cell Physiol 230:1170-80|
|Knowles, Byron C; Weis, Victoria G; Yu, Shiyan et al. (2015) Rab11a regulates syntaxin 3 localization and microvillus assembly in enterocytes. J Cell Sci 128:1617-26|
|Yu, Shiyan; Gao, Nan (2015) Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance. Cell Mol Life Sci 72:3343-53|
|Das, Soumyashree; Yu, Shiyan; Sakamori, Ryotaro et al. (2015) Rab8a vesicles regulate Wnt ligand delivery and Paneth cell maturation at the intestinal stem cell niche. Development 142:2147-62|
|Patel, Chirag; Douard, Veronique; Yu, Shiyan et al. (2015) Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption. FASEB J 29:4046-58|
|Patel, Chirag; Douard, Veronique; Yu, Shiyan et al. (2015) Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK. Am J Physiol Regul Integr Comp Physiol 309:R499-509|
|Yu, Shiyan; Nie, Yingchao; Knowles, Byron et al. (2014) TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis. EMBO J 33:1882-95|
|Yu, Shiyan; Yehia, Ghassan; Wang, Juanfei et al. (2014) Global ablation of the mouse Rab11a gene impairs early embryogenesis and matrix metalloproteinase secretion. J Biol Chem 289:32030-43|
|Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao et al. (2014) CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Res 74:5480-92|