Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

J Exp Med. 2020 Jun 1;217(6):e20191787. doi: 10.1084/jem.20191787.


Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • Animals
  • Cell Line, Tumor
  • Disease Progression
  • Epithelium / enzymology
  • Epithelium / pathology
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mutant Proteins / metabolism
  • Neoplasm Metastasis
  • PTEN Phosphohydrolase / metabolism
  • Prostate / enzymology
  • Prostate / pathology
  • Prostatic Neoplasms / enzymology*
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism


  • Mutant Proteins
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • PTEN Phosphohydrolase