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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 cancers1. Although uncommon in most sporadic cancers2, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines3,4,5. 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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Figure 1: Lung tumours in Kras and Kras Lkb1 L/L mice.
Figure 2: LKB1 suppresses metastasis.


  1. Hearle, N. et al. Frequency and spectrum of cancers in the Peutz–Jeghers syndrome. Clin. Cancer Res. 12, 3209–3215 (2006)

    Article  CAS  Google Scholar 

  2. Forbes, S. et al. Cosmic 2005. Br. J. Cancer 94, 318–322 (2006)

    Article  CAS  Google Scholar 

  3. Sanchez-Cespedes, M. et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659–3662 (2002)

    CAS  PubMed  Google Scholar 

  4. Carretero, J., Medina, P. P., Pio, R., Montuenga, L. M. & Sanchez-Cespedes, M. Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene. Oncogene 23, 4037–4040 (2004)

    Article  CAS  Google Scholar 

  5. Avizienyte, E. et al. LKB1 somatic mutations in sporadic tumors. Am. J. Pathol. 154, 677–681 (1999)

    Article  CAS  Google Scholar 

  6. Tuveson, D. A. & Jacks, T. Modeling human lung cancer in mice: similarities and shortcomings. Oncogene 18, 5318–5324 (1999)

    Article  CAS  Google Scholar 

  7. Hayes, D. N. et al. Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts. J. Clin. Oncol. 24, 5079–5090 (2006)

    Article  CAS  Google Scholar 

  8. Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Entius, M. M. et al. Peutz–Jeghers polyps, dysplasia, and K-ras codon 12 mutations. Gut 41, 320–322 (1997)

    Article  CAS  Google Scholar 

  10. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001)

    Article  CAS  Google Scholar 

  11. Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nature Genet. 29, 418–425 (2001)

    Article  CAS  Google Scholar 

  12. Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996)

    Article  CAS  Google Scholar 

  13. Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001)

    Article  ADS  CAS  Google Scholar 

  14. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Meuwissen, R., Linn, S. C., van der Valk, M., Mooi, W. J. & Berns, A. Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene. Oncogene 20, 6551–6558 (2001)

    Article  CAS  Google Scholar 

  16. Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15, 3249–3262 (2001)

    Article  CAS  Google Scholar 

  17. Jackson, E. L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005)

    Article  CAS  Google Scholar 

  18. Meuwissen, R. et al. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 4, 181–189 (2003)

    Article  CAS  Google Scholar 

  19. Volikos, E. et al. LKB1 exonic and whole gene deletions are a common cause of Peutz–Jeghers syndrome. J. Med. Genet. 43, e18 (2006)

    Article  CAS  Google Scholar 

  20. Karuman, P. et al. The Peutz–Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol. Cell 7, 1307–1319 (2001)

    Article  CAS  Google Scholar 

  21. Raponi, M. et al. Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. Cancer Res. 66, 7466–7472 (2006)

    Article  CAS  Google Scholar 

  22. Hardie, D. G. New roles for the LKB1→AMPK pathway. Curr. Opin. Cell Biol. 17, 167–173 (2005)

    Article  CAS  Google Scholar 

  23. Zhuang, Z. G., Di, G. H., Shen, Z. Z., Ding, J. & Shao, Z. M. Enhanced expression of LKB1 in breast cancer cells attenuates angiogenesis, invasion, and metastatic potential. Mol. Cancer Res. 4, 843–849 (2006)

    Article  CAS  Google Scholar 

  24. Kim, M. et al. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell 125, 1269–1281 (2006)

    Article  CAS  Google Scholar 

  25. Shaw, R. J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004)

    Article  CAS  Google Scholar 

  26. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003)

    Article  ADS  CAS  Google Scholar 

  27. Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007)

    Article  CAS  Google Scholar 

  28. Shipitsin, M. et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 11, 259–273 (2007)

    Article  CAS  Google Scholar 

  29. Matsumoto, S. et al. Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene advance online publication, doi: 10.1038/sj.onc.1210418 (26 March 2007)

  30. Ji, H. et al. K-ras activation generates an inflammatory response in lung tumors. Oncogene 25, 2105–2112 (2006)

    Article  CAS  Google Scholar 

  31. Kozlowski, P. et al. Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype–phenotype correlations. Hum. Genet. 121, 389–400 (2007)

    Article  CAS  Google Scholar 

  32. Sharpless, N. E., Ramsey, M. R., Balasubramanian, P., Castrillon, D. H. & DePinho, R. A. The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis. Oncogene 23, 379–385 (2004)

    Article  CAS  Google Scholar 

  33. Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006)

    Article  ADS  CAS  Google Scholar 

  34. Irizarry, R. A. et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003)

    Article  Google Scholar 

  35. Irizarry, R. A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003)

    Article  Google Scholar 

  36. Bolstad, B. M., Irizarry, R. A., Astrand, M. & Speed, T. P. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003)

    Article  CAS  Google Scholar 

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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.).

Author Contributions The laboratories of N.B., N.E.S. and K.-K.W. contributed equally to this work.

The entire set of unprocessed raw microarray data for both the human and the mouse analyses is available at and through the Gene Expression Omnibus (GSE6135).

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Correspondence to Nabeel Bardeesy, Norman E. Sharpless or Kwok-Kin Wong.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-11 with Legends and Supplementary Tables 1-7. (PDF 3950 kb)

Supplementary Data

This file contains Supplementary Data with the entire list and normalized expression of all 3,275 filtered genes from murine tumor microarray analysis in Supplementary Figure 5. (XLS 1735 kb)

Supplementary Data

This file contains Supplementary Data with the entire list and normalized expression of all 9644 filtered transcripts from A549 and H2126 cell line analysis in Supplementary Figures 8 and 10. (XLS 2095 kb)

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Ji, H., Ramsey, M., Hayes, D. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007).

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