title: The Peutz-Jeghers kinase LKB1 suppresses polyp growth from intestinal cells of a proglucagon-expressing lineage in mice.
abstract: Liver kinase B1 (LKB1; also known as STK11) is a serine/threonine kinase and tumour suppressor that is mutated in Peutz-Jeghers syndrome (PJS), a premalignant syndrome associated with the development of gastrointestinal polyps. Proglucagon-expressing enteroendocrine cells are involved in the control of glucose homeostasis and the regulation of appetite through the secretion of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY). To determine the role of LKB1 in these cells, we bred mice bearing floxed alleles of Lkb1 against animals carrying Cre recombinase under proglucagon promoter control. These mice (GluLKB1KO) were viable and displayed near-normal growth rates and glucose homeostasis. However, they developed large polyps at the gastro-duodenal junction, and displayed premature mortality (death from 120 days of age). Histological analysis of the polyps demonstrated that they had a PJS-like appearance with an arborising smooth-muscle core. Circulating GLP-1 levels were normal in GluLKB1KO mice and the polyps expressed low levels of the peptide, similar to levels in the neighbouring duodenum. Lineage tracing using a Rosa26tdRFP transgene revealed, unexpectedly, that enterocytes within the polyps were derived from non-proglucagon-expressing precursors, whereas connective tissue was largely derived from proglucagon-expressing precursors. Developmental studies in wild-type mice suggested that a subpopulation of proglucagon-expressing cells undergo epithelial-mesenchymal transition (EMT) to become smooth-muscle-like cells. Thus, it is likely that polyps in the GluLKB1KO mice developed from a unique population of smooth-muscle-like cells derived from a proglucagon-expressing precursor. The loss of LKB1 within this subpopulation seems to be sufficient to drive tumorigenesis.
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, W12 ONN, UK.
authors.forename: Sagen
authors.initials: S
authors.lastname: Zac-Varghese
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, W12 ONN, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Trapp
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Richards
authors.affiliation: Department of Cell Biology, Imperial College London, London, W12 ONN, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sayers
authors.affiliation: Department of Cell Biology, Imperial College London, London, W12 ONN, UK.
authors.forename: Gao
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Investigative Medicine, Imperial College London, London, W12 ONN, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: Department of Cell Biology, Imperial College London, London, W12 ONN, UK. g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D007417:Intestinal Polyps / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D052336:Proglucagon / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D052336:Proglucagon; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: Glucagon; LKB1; Peutz-Jeghers