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STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation Granado Martinez, Paula García Ortega, Sara González Sánchez, Elena McGrail Fernández, Kimberley Anne Selgas Sanchis, Rafael Grueso Gragera, Judit Gil Villaverde, Rosa Naldaiz-Gastesi, Neia Rhodes, Ana C Hernandez Losa, Javier Ferrer Fábrega, Berta Canals Suris, Francesc Villanueva Cardús, Josep Mendez Fernández, Olga García-Patos Briones, Vicente Recio Conde, Juan Angel Muñoz Couselo, Eva Institut Català de la Salut [Granado-Martínez P, Garcia-Ortega S, González-Sánchez E, McGrail K, Selgas R, Gil R, Recio JA] Grup de Recerca Biomèdica en Melanoma. Models Animals de Càncer, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Grueso J] Grup de Recerca Biomèdica en Melanoma. Models Animals de Càncer, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Naldaiz-Gastesi N] Grup de Recerca Biomèdica en Melanoma. Models Animals de Càncer, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Biodonostia, Neurosciences Area, Group of Neuromuscular Diseases, San Sebastian 20014, Spain. [Rhodes AC] Grup de Recerca Biomèdica en Melanoma. Models Animals de Càncer, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, 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] Servei d’Anatomia Patològica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Ferrer B] Grup de Recerca Biomèdica en Melanoma. Models Animals de Càncer, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei d’Anatomia Patològica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Canals F] Proteomics Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Villanueva J, Méndez O] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Muñoz-Couselo E] Grup de Recerca Biomèdica en Melanoma. Models Animals de Càncer, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Clinical Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain Vall d'Hebron Barcelona Hospital Campus Càncer - Aspectes genètics Regulació genètica DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms::Neoplasms by Histologic Type::Neoplasms::Neoplasms by Histologic Type::Nevi and Melanomas::Melanoma Other subheadings::Other subheadings::Other subheadings::/genetics PHENOMENA AND PROCESSES::Genetic Phenomena::Gene Expression Regulation::Gene Expression Regulation, Neoplastic FENÓMENOS Y PROCESOS::fenómenos genéticos::regulación de la expresión génica::regulación de la expresión génica neoplásica ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias::neoplasias por tipo histológico::neoplasias::neoplasias por tipo histológico::nevos y melanomas::melanoma Otros calificadores::Otros calificadores::Otros calificadores::/genética Genètica del càncer; Càncer de pulmó; Oncògens Genética del cáncer; Cáncer de pulmón; Oncogenes Cancer genetics; Lung cancer; Oncogenes 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. This work was supported by funds from the Spanish Health Ministry (Fondo de Investigaciones Sanitarias-FIS) PI1400375-Fondos FEDER, PI17/00043-Fondos FEDER, Euronanomed2-ISCIII (AC16/00019)-Fondos FEDER, Asociación Española Contra el Cancer (AECC-GCB15152978SOEN) supported PGM, KM., Ramón Areces Foundation supported KM and research. 2021-09-03T10:12:27Z 2021-09-03T10:12:27Z 2020-07-09 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Granado-Martínez P, Garcia-Ortega S, González-Sánchez E, McGrail K, Selgas R, Grueso J, et al. STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation. Commun Biol. 2020 Jul 9;3:366. 2399-3642 https://hdl.handle.net/11351/6261 10.1038/s42003-020-1092-0 32647375 000552080500009 eng Communications Biology;3 https://doi.org/10.1038/s42003-020-1092-0 info:eu-repo/grantAgreement/ES/PE2013-2016/PI14%2F00375 info:eu-repo/grantAgreement/ES/PE2013-2016/PI17%2F00043 info:eu-repo/grantAgreement/ES/PE2013-2016/AC16%2F00019 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf Nature Research Scientia