LKB1 modulates lung cancer differentiation and metastasis.
Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.
Ji
Hongbin
H
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
Ramsey
Matthew R
MR
Hayes
D Neil
DN
Fan
Cheng
C
McNamara
Kate
K
Kozlowski
Piotr
P
Torrice
Chad
C
Wu
Michael C
MC
Shimamura
Takeshi
T
Perera
Samanthi A
SA
Liang
Mei-Chih
MC
Cai
Dongpo
D
Naumov
George N
GN
Bao
Lei
L
Contreras
Cristina M
CM
Li
Danan
D
Chen
Liang
L
Krishnamurthy
Janakiraman
J
Koivunen
Jussi
J
Chirieac
Lucian R
LR
Padera
Robert F
RF
Bronson
Roderick T
RT
Lindeman
Neal I
NI
Christiani
David C
DC
Lin
Xihong
X
Shapiro
Geoffrey I
GI
Jänne
Pasi A
PA
Johnson
Bruce E
BE
Meyerson
Matthew
M
Kwiatkowski
David J
DJ
Castrillon
Diego H
DH
Bardeesy
Nabeel
N
Sharpless
Norman E
NE
Wong
Kwok-Kin
KK
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology; D019942:Genes, p16; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases