title: Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Aguirre
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.forename: Jean X
authors.initials: JX
authors.lastname: Zhang
authors.forename: Ergun
authors.initials: E
authors.lastname: Sahin
authors.forename: Giminna
authors.initials: G
authors.lastname: Yeo
authors.forename: Aditya
authors.initials: A
authors.lastname: Ponugoti
authors.forename: Roustem
authors.initials: R
authors.lastname: Nabioullin
authors.forename: Scott
authors.initials: S
authors.lastname: Deroo
authors.forename: Shenghong
authors.initials: S
authors.lastname: Yang
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Wang
authors.forename: John P
authors.initials: JP
authors.lastname: McGrath
authors.forename: Marina
authors.initials: M
authors.lastname: Protopopova
authors.forename: Elena
authors.initials: E
authors.lastname: Ivanova
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.forename: Ming S
authors.initials: MS
authors.lastname: Tsao
authors.forename: Mark
authors.initials: M
authors.lastname: Redston
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010183:Pancreatic Ducts / Q000166:cytology / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C116367:PAK4 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C534426:RIO kinase 3, human; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins