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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases
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Animals
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CD24 Antigen / genetics*
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CD24 Antigen / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cells, Cultured
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Dasatinib
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Immunoblotting
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Melanocytes / drug effects
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Melanocytes / metabolism
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Melanoma / genetics*
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Nude
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Mutation
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Neoplasm Metastasis
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-yes / genetics*
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Proto-Oncogene Proteins c-yes / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics*
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Proto-Oncogene Proteins p21(ras) / metabolism
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Pyrimidines / pharmacology
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Thiazoles / pharmacology
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Transplantation, Heterologous
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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CD24 Antigen
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Cd24a protein, mouse
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Protein Kinase Inhibitors
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Pyrimidines
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Thiazoles
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-yes
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Yes1 protein, mouse
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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AMP-Activated Protein Kinases
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)
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Dasatinib