LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma

Wenjin Liu, Kimberly B. Monahan, Adam D. Pfefferle, Takeshi Shimamura, Jessica Sorrentino, Keefe T. Chan, David W. Roadcap, David W. Ollila, Nancy E. Thomas, Diego H. Castrillon, C. Ryan Miller, Charles M. Perou, Kwok Kin Wong, James E. Bear, Norman E. Sharpless

Research output: Contribution to journalArticle

84 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)751-764
Number of pages14
JournalCancer Cell
Volume21
Issue number6
DOIs
StatePublished - Jun 12 2012

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Liu, W., Monahan, K. B., Pfefferle, A. D., Shimamura, T., Sorrentino, J., Chan, K. T., Roadcap, D. W., Ollila, D. W., Thomas, N. E., Castrillon, D. H., Miller, C. R., Perou, C. M., Wong, K. K., Bear, J. E., & Sharpless, N. E. (2012). LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma. Cancer Cell, 21(6), 751-764. https://doi.org/10.1016/j.ccr.2012.03.048