Elucidating the contribution of somatic mutations to cancer is essential for personalized medicine. STK11 (LKB1) appears to be inactivated in human cancer. However, somatic missense mutations also occur, and the role/s of these alterations to this disease remain unknown. Here, we investigated the contribution of four missense LKB1 somatic mutations in tumor biology. Three out of the four mutants lost their tumor suppressor capabilities and showed deficient kinase activity. The remaining mutant retained the enzymatic activity of wild type LKB1, but induced increased cell motility. Mechanistically, LKB1 mutants resulted in differential gene expression of genes encoding vesicle trafficking regulating molecules, adhesion molecules and cytokines. The differentially regulated genes correlated with protein networks identified through comparative secretome analysis. Notably, three mutant isoforms promoted tumor growth, and one induced inflammation-like features together with dysregulated levels of cytokines. These findings uncover oncogenic roles of LKB1 somatic mutations, and will aid in further understanding their contributions to cancer development and progression.

阐明体细胞突变对癌症的贡献对于个性化医学至关重要。STK11（LKB1）似乎已在人类癌症中失活。然而，体细胞错义突变也发生，并且这些改变对该疾病的作用仍然未知。在这里，我们调查了四个错义LKB1体细胞突变在肿瘤生物学中的贡献。四个突变体中的三个失去了其抑癌能力，并显示出不足的激酶活性。其余的突变体保留了野生型LKB1的酶活性，但诱导了细胞运动性的增加。从机制上讲，LKB1突变体导致编码小泡运输调节分子，粘附分子和细胞因子的基因的差异基因表达。差异调节的基因与通过比较分泌组分析鉴定的蛋白质网络相关。值得注意的是，三种突变体同工型促进了肿瘤的生长，一种诱发炎症样特征以及细胞因子水平失调。这些发现揭示了LKB1体细胞突变的致癌作用，并将有助于进一步了解其对癌症发展和进展的贡献。