LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis

Science. 2018 Jul 27;361(6400):406-411. doi: 10.1126/science.aan3975.

Abstract

Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/- mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/- animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyps / genetics*
  • Adenomatous Polyps / immunology
  • Adenomatous Polyps / pathology
  • Animals
  • Chemokine CXCL2 / genetics
  • Gene Deletion
  • Gene Expression
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-11 / genetics
  • Interleukin-6 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Peutz-Jeghers Syndrome / genetics*
  • Peutz-Jeghers Syndrome / immunology
  • Peutz-Jeghers Syndrome / pathology
  • Protein-Serine-Threonine Kinases / genetics*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / pathology
  • T-Lymphocytes / immunology*

Substances

  • Chemokine CXCL2
  • Interleukin-11
  • Interleukin-6
  • STAT3 Transcription Factor
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases

Supplementary concepts

  • Polyposis, Gastric

Grant support