Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer.
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.
Kimmelman
Alec C
AC
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Hezel
Aram F
AF
Aguirre
Andrew J
AJ
Zheng
Hongwu
H
Paik
Ji-Hye
JH
Ying
Haoqiang
H
Chu
Gerald C
GC
Zhang
Jean X
JX
Sahin
Ergun
E
Yeo
Giminna
G
Ponugoti
Aditya
A
Nabioullin
Roustem
R
Deroo
Scott
S
Yang
Shenghong
S
Wang
Xiaoxu
X
McGrath
John P
JP
Protopopova
Marina
M
Ivanova
Elena
E
Zhang
Jianhua
J
Feng
Bin
B
Tsao
Ming S
MS
Redston
Mark
M
Protopopov
Alexei
A
Xiao
Yonghong
Y
Futreal
P Andrew
PA
Hahn
William C
WC
Klimstra
David S
DS
Chin
Lynda
L
DePinho
Ronald A
RA
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
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