LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma

Cancer Cell. 2012 Jun 12;21(6):751-64. doi: 10.1016/j.ccr.2012.03.048.

Abstract

Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24(+) cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24(-) cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24(+) tumor subpopulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD24 Antigen / genetics*
  • CD24 Antigen / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dasatinib
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoblotting
  • Melanocytes / drug effects
  • Melanocytes / metabolism
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mice, Nude
  • Mutation
  • Neoplasm Metastasis
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-yes / genetics*
  • Proto-Oncogene Proteins c-yes / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Pyrimidines / pharmacology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiazoles / pharmacology
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • CD24 Antigen
  • Cd24a protein, mouse
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Tumor Suppressor Protein p53
  • Stk11 protein, mouse
  • Proto-Oncogene Proteins c-yes
  • Yes1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Dasatinib

Associated data

  • GEO/GSE34866