Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 49; pp. 19372 - 19377
• Main Authors: Kimmelman, Alec C, Hezel, Aram F, Aguirre, Andrew J, Zheng, Hongwu, Paik, Ji-hye, Ying, Haoqiang, Chu, Gerald C, Zhang, Jean X, Sahin, Ergun, Yeo, Giminna, Ponugoti, Aditya, Nabioullin, Roustem, Deroo, Scott, Yang, Shenghong, Wang, Xiaoxu, McGrath, John P, Protopopova, Marina, Ivanova, Elena, Zhang, Jianhua, Feng, Bin, Tsao, Ming S, Redston, Mark, Protopopov, Alexei, Xiao, Yonghong, Futreal, P. Andrew, Hahn, William C, Klimstra, David S, Chin, Lynda, DePinho, Ronald A
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.12.2008; National Acad Sciences
• Subjects: Animals; Biological Sciences; Cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Cell adhesion & migration; Cell Line, Transformed; Cell lines; Cell motility; Cell Movement - physiology; Epithelial cells; Gene Expression Regulation, Neoplastic; Genomics; Genotype & phenotype; Humans; Kinases; Mice; Mice, Nude; Neoplasm Invasiveness; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; Pancreatic cancer; Pancreatic cells; Pancreatic Ducts - cytology; Pancreatic Ducts - physiology; Pancreatic neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phenotype; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism; Signal Transduction - physiology; Small interfering RNA; Tumor cell line; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0809966105

Pancreas ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically presents as advanced, unresectable disease. This invasive tendency, coupled with intrinsic resistance to standard therapies and genome instability, are major contributors to poor long-term survival. The genetic elements governing the invasive propensity of PDAC have not been well elucidated. Here, in the course of validating resident genes in highly recurrent and focal amplifications in PDAC, we have identified Rio Kinase 3 (RIOK3) as an amplified gene that alters cytoskeletal architecture as well as promotes pancreatic ductal cell migration and invasion. We determined that RIOK3 promotes its invasive activities through activation of the small G protein, Rac. This genomic and functional link to Rac signaling prompted a genome wide survey of other components of the Rho family network, revealing p21 Activated Kinase 4 (PAK4) as another amplified gene in PDAC tumors and cell lines. Like RIOK3, PAK4 promotes pancreas ductal cell motility and invasion. Together, the genomic and functional profiles establish the Rho family GTP-binding proteins as integral to the hallmark invasive nature of this lethal disease.