STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation.
Paula Granado-MartínezSara García-OrtegaElena González-SánchezKimberley McGrailRafael SelgasJudit GruesoRosa GilNeia Naldaiz-GastesiAna C RhodesJavier Hernandez-LosaBerta FerrerFrancesc CanalsJosep VillanuevaOlga MéndezSergio Espinosa-GilJose Miguel LizcanoEva Muñoz-CouseloVicente García-Patos BrionesJuan Ángel RecioPublished in: Communications biology (2020)
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.
Keyphrases
- wild type
- papillary thyroid
- gene expression
- copy number
- squamous cell
- oxidative stress
- intellectual disability
- endothelial cells
- genome wide
- high glucose
- dna methylation
- diabetic rats
- biofilm formation
- transcription factor
- squamous cell carcinoma
- nitric oxide
- mass spectrometry
- cell therapy
- childhood cancer
- mesenchymal stem cells
- cystic fibrosis
- bone marrow
- amino acid
- pseudomonas aeruginosa
- stem cells
- data analysis
- induced pluripotent stem cells
- cell adhesion
- protein kinase
- atomic force microscopy