Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain.
Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, 08035, Spain.
Commun Biol. 2020 Jul 9;3(1):366. doi: 10.1038/s42003-020-1092-0.
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疗至关重要。STK11（LKB1）似乎在人类癌症中失活。然而，也会发生体细胞错义突变，这些改变对这种疾病的作用/仍然未知。在这里，我们研究了四个错义 LKB1 体细胞突变在肿瘤生物学中的贡献。这四个突变体中的三个失去了肿瘤抑制能力，并且显示出激酶活性不足。剩下的突变体保留了野生型 LKB1 的酶活性，但诱导了增加的细胞迁移。从机制上讲，LKB1 突变导致编码囊泡运输调节分子、粘附分子和细胞因子的基因的差异表达。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肿瘤生长，一种诱导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它们对癌症发展和进展的贡献。
