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

Correspondence to: Nabeel Bardeesy¹⁶Norman E. Sharpless^10,11,12Kwok-Kin Wong^1,7 Correspondence and requests for materials should be addressed to K.-K.W. (Email: kwong1@partners.org) or N.E.S. (Email: nes@med.unc.edu) or N.B. (Email: nelbardeesy@partners.org).

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 cancers¹. Although uncommon in most sporadic cancers², inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines^{3, 4, 5}. 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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