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Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation

Nature volume 419, pages 162–167 (2002)Cite this article

Abstract

Germline mutations in LKB1 (also known as STK11) are associated with Peutz–Jeghers syndrome (PJS), a disorder with predisposition to gastrointestinal polyposis and cancer1. PJS polyps are unusual neoplasms characterized by marked epithelial and stromal overgrowth but have limited malignant potential2. Here we show that Lkb1+/- mice develop intestinal polyps identical to those seen in individuals affected with PJS. Consistent with this in vivo tumour suppressor function, Lkb1 deficiency prevents culture-induced senescence without loss of Ink4a/Arf or p53. Despite compromised mortality, Lkb1-/- mouse embryonic fibroblasts show resistance to transformation by activated Ha-Ras either alone or with immortalizing oncogenes. This phenotype is in agreement with the paucity of mutations in Ras seen in PJS polyps3,4 and suggests that loss of Lkb1 function as an early neoplastic event renders cells resistant to subsequent oncogene-induced transformation. In addition, the Lkb1 transcriptome shows modulation of factors linked to angiogenesis, extracellular matrix remodelling, cell adhesion and inhibition of Ras transformation. Together, our data rationalize several features of PJS polyposis—notably its peculiar histopathological presentation and limited malignant potential—and place Lkb1 in a distinct class of tumour suppressors.

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Figure 1: Targeting strategy and analysis of Lkb1.
Figure 2: Gastrointestinal polyps in Lkb1+/- mice.
Figure 3: Lkb1-/- MEF immortalization studies.
Figure 4: Lkb1-/- cells are resistant to oncogenic transformation.
Figure 5: Lkb1-/- expression profile.

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Acknowledgements

We thank L. Ritchie and J. Horner of DFCI mouse core for advice and assistance; S. Dymecki, H. Westphal, M. Oren, S. Lowe, D. Silver, C. Der & J. DeCaprio for advice and reagents; and D. Livingston, J. DeCaprio and W. Kaelin for comments on the manuscript. N.B. is supported by the ACS John Peter Hoffman Award and the Liss Family Fund grant for research in pancreatic cancer. R.A.D. is an American Cancer Society Professor and recipient of the Steven and Michele Kirsch Foundation Investigator Award. This work was supported by grants from the NCI (National Cancer Institute) and ACS (American Cancer Society).

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Authors and Affiliations

  1. Department of Adult Oncology, Dana-Farber Cancer Institute and Departments of Medicine and Genetics, Harvard Medical School, Massachusetts, 02115, Boston, USA

    Nabeel Bardeesy, Manisha Sinha, Aram F. Hezel, Nathaniel A. Hathaway, Norman E. Sharpless & Ronald A. DePinho

  2. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Massachusetts, 02115, Boston, USA

    Sabina Signoretti, Massimo Loda & Daniel R. Carrasco

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  1. Nabeel Bardeesy
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Correspondence to Ronald A. DePinho.

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Bardeesy, N., Sinha, M., Hezel, A. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002). https://doi.org/10.1038/nature01045

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