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LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis

Pekka Katajisto1, Kari Vaahtomeri, Niklas Ekman

  • 1Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, 00014 University of Helsinki, Finland.

Nature Genetics
|March 4, 2008
PubMed

Insights

Germline mutations in STK11 (also known as LKB1) cause Peutz-Jeghers syndrome (PJS). This study reveals that loss of STK11 in mesenchymal cells drives PJS gastrointestinal polyp formation and TGF-beta signaling defects.

Area of Science:

  • Oncology
  • Gastroenterology
  • Genetics

Background:

  • Peutz-Jeghers syndrome (PJS) is linked to germline STK11 (LKB1) mutations.
  • PJS polyps have a significant stromal component, suggesting non-epithelial origins.
  • Loss of heterozygosity is not always observed in human PJS polyps.

Purpose of the Study:

  • To investigate the role of STK11 in mesenchymal cells in PJS tumorigenesis.
  • To determine if mesenchymal STK11 loss can cause PJS-like gastrointestinal polyps.
  • To explore the mechanism of STK11-driven tumorigenesis involving TGF-beta signaling.

Main Methods:

  • Utilized mouse models with targeted STK11 loss in Tagln-expressing mesenchymal cells.
  • Analyzed the resulting gastrointestinal polyps for histological and molecular similarities to human PJS.
  • Assessed TGF-beta production and signaling in STK11-deficient mesenchymal cells and epithelial cells.

Main Results:

  • Monoallelic or biallelic STK11 loss in mesenchymal cells led to PJS-like gastrointestinal polyps and premature death.
  • STK11-deficient mesenchymal cells exhibited reduced TGF-beta production.
  • Defective TGF-beta signaling in mesenchymal cells correlated with increased epithelial cell proliferation.

Conclusions:

  • Mesenchymal STK11 loss is sufficient to cause PJS-like gastrointestinal polyps.
  • Defective stromal TGF-beta signaling is a key mechanism in PJS tumorigenesis.
  • This stromal-derived mechanism of tumor suppression is relevant to human PJS.

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