TY - JOUR
T1 - LKB1 modulates lung cancer differentiation and metastasis
AU - Ji, Hongbin
AU - Ramsey, Matthew R.
AU - Hayes, D. Neil
AU - Fan, Cheng
AU - McNamara, Kate
AU - Kozlowski, Piotr
AU - Torrice, Chad
AU - Wu, Michael C.
AU - Shimamura, Takeshi
AU - Perera, Samanthi A.
AU - Liang, Mei Chih
AU - Cai, Dongpo
AU - Naumov, George N.
AU - Bao, Lei
AU - Contreras, Cristina M.
AU - Li, Danan
AU - Chen, Liang
AU - Krishnamurthy, Janakiraman
AU - Koivunen, Jussi
AU - Chirieac, Lucian R.
AU - Padera, Robert F.
AU - Bronson, Roderick T.
AU - Lindeman, Neal I.
AU - Christiani, David C.
AU - Lin, Xihong
AU - Shapiro, Geoffrey I.
AU - Jänne, Pasi A.
AU - Johnson, Bruce E.
AU - Meyerson, Matthew
AU - Kwiatkowski, David J.
AU - Castrillon, Diego H.
AU - Bardeesy, Nabeel
AU - Sharpless, Norman E.
AU - Wong, Kwok Kin
N1 - Funding Information:
Acknowledgements We thank G. Tonon, C. Perou, W. Kim and the Harvard lung SPORE group for advice and discussions; J. Yokota for sharing unpublished data; and W. Winckler, R. Mukundhan, S. Zaghlul, H. Xia, B. L. Jung, M. Zheng and C. Lam for technical support. We acknowledge the technical assistance of the UNC Tissue Procurement Core Facility, an NCI-designated core laboratory. This work was supported by the NIH (NIA and NCI), the Sidney Kimmel Foundation for Cancer Research (D.H.C., K.-K.W. and N.E.S.), the American Federation of Aging (N.E.S.), the Joan Scarangello Foundation to Conquer Lung Cancer (K.-K.W.), the Flight Attendant Medical Research Institute (K.-K.W.), the Waxman Foundation (N.B.), the Harvard Stem Cell Institute (N.B.), and the Linda Verville Foundation (N.B.).
PY - 2007/8/16
Y1 - 2007/8/16
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=34547926839&partnerID=8YFLogxK
U2 - 10.1038/nature06030
DO - 10.1038/nature06030
M3 - Article
C2 - 17676035
AN - SCOPUS:34547926839
SN - 0028-0836
VL - 448
SP - 807
EP - 810
JO - Nature
JF - Nature
IS - 7155
ER -