STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation.

Autor: Granado-Martínez P; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., Garcia-Ortega S; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., González-Sánchez E; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., McGrail K; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., Selgas R; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., Grueso J; 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., Gil R; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., Naldaiz-Gastesi N; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain.; Biodonostia, Neurosciences Area, Group of Neuromuscular Diseases, San Sebastian, 20014, Spain., Rhodes AC; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain.; Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain., Hernandez-Losa J; Anatomy Pathology Department, Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., Ferrer B; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain.; Anatomy Pathology Department, Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., Canals F; Proteomics Laboratory, Vall d'Hebron Institute of Oncology (VHIO, Barcelona, 08035, Spain., Villanueva J; Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO, Barcelona, 08035, Spain., Méndez O; Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO, Barcelona, 08035, Spain., Espinosa-Gil S; Protein Kinases and Signal Transduction Laboratory, Neuroscience Institute and Molecular Biology and Biochemistry Department, UAB, Bellaterra, Barcelona, 08193, Spain., Lizcano JM; Protein Kinases and Signal Transduction Laboratory, Neuroscience Institute and Molecular Biology and Biochemistry Department, UAB, Bellaterra, Barcelona, 08193, Spain., Muñoz-Couselo E; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain.; Clinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital, Barcelona-UAB, Barcelona, 08035, Spain., García-Patos V; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain.; Dermatology Department, Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain., Recio JA; Biomedical Research in Melanoma-Animal Models and Cancer Laboratory- Vall d'Hebron Research Institute VHIR-Vall d'Hebron Hospital Barcelona-UAB, Barcelona, 08035, Spain. juan.recio@vhir.org.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2020 Jul 09; Vol. 3 (1), pp. 366. Date of Electronic Publication: 2020 Jul 09.
DOI: 10.1038/s42003-020-1092-0
Abstrakt: 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.
Databáze: MEDLINE
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