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

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• 作者：Wenjin Liu¹ ; Kimberly  ; B. Monahan¹ ; Adam  ; D. Pfefferle² ; Takeshi Shimamura⁹ ; Jessica Sorrentino¹ ; Keefe  ; T. Chan³ ; ⁴ ; David  ; W. Roadcap³ ; David  ; W. Ollila⁷ ; Nancy  ; E. Thomas⁶ ; Diego  ; H. Castrillon¹⁰ ; C.  ; Ryan Miller² ; Charles  ; M. Perou¹ ; ² ; ⁸ ; Kwok-Kin Wong¹¹ ; James  ; E. Bear³ ; ⁴ ; Norman  ; E. Sharpless¹ ; ⁵ ; ^{nes@med.unc.edu}
• 刊名：Cancer Cell
• 出版年：2012
• 期刊代码：43_15356108
• 类别：med
• 出版时间：12 June, 2012
• 卷：21
• 期：6
• 页码：751-764
• 文件大小：1981 K

摘要

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Summary

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 (卤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,聽and expansion of a CD24⁺ cell population, which showed increased metastatic behavior in聽vitro and in聽vivo relative to isogenic CD24^{鈭?/sup> 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.}