Abstract
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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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We thank G. Tonon, C. Perou, W. Kim and the Harvard lung SPORE group for advice and discussions; J. Yokota for sharing unpublished data; and W. Winckler, R. Mukundhan, S. Zaghlul, H. Xia, B. L. Jung, M. Zheng and C. Lam for technical support.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.).
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 http://genome.unc.edu and through the Gene Expression Omnibus (GSE6135).
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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). https://doi.org/10.1038/nature06030
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DOI: https://doi.org/10.1038/nature06030
