Author/Authors :
Liu، نويسنده , , Wenjin and Monahan، نويسنده , , Kimberly B. and Pfefferle، نويسنده , , Adam D. and Shimamura، نويسنده , , Takeshi and Sorrentino، نويسنده , , Jessica and Chan، نويسنده , , Keefe T. and Roadcap، نويسنده , , David W. and Ollila، نويسنده , , David W. and Thomas، نويسنده , , Nancy E. and Castrillon، نويسنده , , Diego H. and Miller، نويسنده , , C. Ryan and Perou، نويسنده , , Charles M. and Wong، نويسنده , , Kwok-Kin and Bear، نويسنده , , James E. and Sharpless، نويسنده , , Norman E.، نويسنده ,
Abstract :
Summary
ne 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.
