LKB1 modulates lung cancer differentiation and metastasis

Ji, Hongbin
Ramsey, Matthew R.
Hayes, D. Neil
Fan, Cheng
McNamara, Kate
Kozlowski, Piotr
Torrice, Chad
Wu, Michael C.
Shimamura, Takeshi
Perera, Samanthi A.
Liang, Mei-Chih
Cai, Dongpo
Naumov, George N.
Bao, Lei
Contreras, Cristina M.
Li, Danan
Chen, Liang
Krishnamurthy, Janakiraman
Koivunen, Jussi
Chirieac, Lucian R.
Padera, Robert F.
Bronson, Roderick T.
Lindeman, Neal I.
Christiani, David C.
Lin, Xihong
Shapiro, Geoffrey I.
Jänne, Pasi A.
Johnson, Bruce E.
Meyerson, Matthew
Kwiatkowski, David J.
Castrillon, Diego H.
Bardeesy, Nabeel
Sharpless, Norman E.
Wong, Kwok-Kin

¹Department of Medical Oncology, Dana-Farber Cancer Institute, ²Department of Environmental Health, ³Department of Biostatistics, Harvard School of Public Health, ⁴Ludwig Center at Dana-Farber/Harvard Cancer Center, ⁵Division of Translational Medicine, ⁶Department of Pathology, ⁷Department of Medicine, Brigham and Women's Hospital, ⁸Department of Surgery, Children's Hospital, ⁹Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. ¹⁰Department of Genetics, ¹¹Department of Medicine, ¹²Curriculum in Genetics and Molecular Biology, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA. ¹³Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. ¹⁴Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, USA. ¹⁵Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ¹⁶Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

doi:10.1038/nature06030

*These authors contributed equally to this work.

Received 15 March; accepted 19 June 2007.

Published online 5 August 2007.

Supplementary Information is linked to the online version of the paper at www.nature.com/nature.

Author Information The entire set of unprocessed raw microarray data for both the human and the mouse analyses is available at http://genome.unc.edu and through the Gene Expression Omnibus (GSE6135). Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to K.-K.W. ([email protected]) or N.E.S. ([email protected]) or N.B. ([email protected]).

Nature 448(7155):p 807-810, August 16, 2007. | DOI: 10.1038/nature06030

Germline mutation in serine/threonine kinase 11 (STK11,also calledLKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations ofLKB1have 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 ofLkb1to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss ofp53orInk4a/Arf(also known asCdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation ofLkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lackingp53orInk4a/Arf.Pulmonary tumorigenesis was also accelerated by hemizygous inactivation ofLkb1.Consistent with these findings, inactivation ofLKB1was 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.