Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer Academic Article uri icon

Overview

MeSH Major

  • Carcinoma, Pancreatic Ductal
  • Pancreatic Ducts
  • Pancreatic Neoplasms
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • rho GTP-Binding Proteins

abstract

  • 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.

publication date

  • December 9, 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2614768

Digital Object Identifier (DOI)

  • 10.1073/pnas.0809966105

PubMed ID

  • 19050074

Additional Document Info

start page

  • 19372

end page

  • 7

volume

  • 105

number

  • 49