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

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Authors: 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.
Article Title: LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma
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.
Journal Title: Cancer cell
Volume: 21
Issue: 6
ISSN: 1878-3686; 1535-6108
Publisher: Elsevier Inc  
Journal Place: United States
Date Published: 2012
Start Page: 751
End Page: 764
Language: eng
DOI/URL:

10.1016/j.ccr.2012.03.048
Notes: LR: 20141016; CI: Copyright (c) 2012; GEO/GSE34866; GR: P01 CA154303/CA/NCI NIH HHS/United States; GR: P30 CA016086/CA/NCI NIH HHS/United States; GR: R01 CA122794/CA/NCI NIH HHS/United States; GR: R01 CA137181/CA/NCI NIH HHS/United States; GR: R01 CA140594/CA/NCI NIH HHS/United States; GR: R01 CA163896/CA/NCI NIH HHS/United States; GR: T32 ES007126/ES/NIEHS NIH HHS/United States; JID: 101130617; 0 (Antigens, CD24); 0 (Cd24a protein, mouse); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (Thiazoles); 0 (Tumor Suppressor Protein p53); EC 2.7.1.- (Stk11 protein, mouse); EC 2.7.10.2 (Proto-Oncogene Proteins c-yes); EC 2.7.10.2 (Yes1 protein, mouse); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 3.6.5.2 (Kras2 protein, mouse); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)); RBZ1571X5H (dasatinib); NIHMS442574; OID: NLM: NIHMS442574; OID: NLM: PMC3660964; 2011/07/29 [received]; 2012/01/20 [revised]; 2012/03/28 [accepted]; ppublish