LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma.
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.
Department of Genetics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA.
Wenjin
W
Liu
Kimberly B
KB
Monahan
Adam D
AD
Pfefferle
Takeshi
T
Shimamura
Jessica
J
Sorrentino
Keefe T
KT
Chan
David W
DW
Roadcap
David W
DW
Ollila
Nancy E
NE
Thomas
Diego H
DH
Castrillon
C Ryan
CR
Miller
Charles M
CM
Perou
Kwok-Kin
KK
Wong
James E
JE
Bear
Norman E
NE
Sharpless
D055372:AMP-Activated Protein Kinases; D000818:Animals; D051927:CD24 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D051927:CD24 Antigen; C497890:Cd24a protein, mouse; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D051575:Proto-Oncogene Proteins c-yes; C496639:Yes1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000069439:Dasatinib