LKB1/STK11 Inactivation Leads to Expansion of Pro-Metastatic Tumor Sub-Population in Melanoma. Mus musculus

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 and the subsequent 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 a SFK-dependent expansion of a pro-metastatic, CD24+ tumor sub-population Overall design: reference x sample

LKB1（STK11）生殖系突变与Peutz–Jeghers综合征（PJS）相关，该综合征以黏膜皮肤色素沉着异常为特征；体细胞LKB1突变则存在于10%的皮肤黑色素瘤病例中。本研究通过在小鼠黑色素细胞中结合K-Ras激活（伴或不伴p53缺失）体细胞失活Lkb1，成功构建了具有100%外显率的多色素化高转移性黑色素瘤模型。研究发现，LKB1缺陷可升高SRC家族激酶（SRC-family kinase, SFK）YES的磷酸化水平，进而引发CD24+细胞群扩增；相较于同基因背景的CD24-细胞，该细胞群在体外及体内均表现出更强的转移潜能。上述结果表明，在RAS激活的背景下，LKB1失活可通过依赖SFK的方式扩增促转移CD24+肿瘤亚群，从而促进肿瘤转移。整体实验设计：参照样本与实验样本