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

Nabeel Bardeesy, Manisha Sinha, Aram F. Hezel, Sabina Signoretti, Nathaniel A. Hathaway, Norman E. Sharpless, Massimo Loda, Daniel R. Carrasco and Ronald A. DePinho ()
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Nabeel Bardeesy: Harvard Medical School
Manisha Sinha: Harvard Medical School
Aram F. Hezel: Harvard Medical School
Sabina Signoretti: Harvard Medical School
Nathaniel A. Hathaway: Harvard Medical School
Norman E. Sharpless: Harvard Medical School
Massimo Loda: Harvard Medical School
Daniel R. Carrasco: Harvard Medical School
Ronald A. DePinho: Harvard Medical School

Nature, 2002, vol. 419, issue 6903, 162-167

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature01045

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