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| Home > Articles > Published articles > Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer |
| Home > Articles > Published articles > Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer |
(Basque Research and Technology Alliance (BRTA)) (Institut de Recerca Biomèdica) (Centro de Investigación Biomédica en Red de Cáncer) (Institut de Recerca Biomèdica) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (The Institute of Cancer Research (London, Regne Unit)) (The Institute of Cancer Research (London, Regne Unit)) (Centro de Investigación Biomédica en Red de Cáncer) (Institut de Recerca Biomèdica) (Universidad del País Vasco) (Centro de Investigación Biomédica en Red de Cáncer) (Universidad Complutense de Madrid. Departamento de Bioquímica y Biología Molecular) (Basque Research and Technology Alliance (BRTA)) (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos) (Universidad del País Vasco. Departamento de Bioquímica y Biología Molecular) (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (Espanya)) (Basque Research and Technology Alliance (BRTA)) (Basque Research and Technology Alliance (BRTA)) (The Royal Marsden National Health Service Foundation Trust (London, Regne Unit)) (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (Espanya)) (Charles University (Praga, República Txeca). Department of Paediatric Haematology/Oncology) (Institut d'Investigació Biomèdica de Bellvitge) (Ikerbasque, Basque Foundation for Science (Bilbao, País Basc))
| Date: | 2020 |
| Abstract: | This study unravels an unprecedented murine model of lethal metastatic prostate cancer, based on the combined deletion of Pten and Lkb1. Importantly, minimal activity of LKB1 is sufficient to hamper prostate cancer cell aggressiveness, thus redefining the relationship between gene dosage and tumor suppression. Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1 K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination. |
| Grants: | Ministerio de Ciencia e Innovación RTI2018-097267-B-100 Ministerio de Ciencia e Innovación SAF2016-79381-R Ministerio de Ciencia e Innovación SAF2016-81975-REDT European Commission 336343 European Commission 819242 European Commission 754627 European Commission 721532 Ministerio de Ciencia e Innovación SAF2015-66015-R Ministerio de Ciencia e Innovación CB16-12-00228 Ministerio de Ciencia e Innovación SAF2016-79847-R Ministerio de Ciencia e Innovación BFU2017-84653-P Ministerio de Ciencia e Innovación SEV-2016-0644 Instituto de Salud Carlos III PI18-00442 Instituto de Salud Carlos III PI15-00339 Ministerio de Ciencia e Innovación SAF2015-64237-R Ministerio de Ciencia e Innovación SAF016-76008R |
| Note: | Altres ajuts: V. Torrano is funded by Fundación Vasca de Innovación e Investigación Sanitarias, Bioef (BIO15/CA/052), the Fundación Científica Asociación Española Contra el Cáncer J.P. Bizkaia, and the Basque Department of Health (2016111109). The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek), the Department of Education (IKERTALDE IT1106-16, with A. Gomez-Muñoz), the Department of Health (2019222031), the Fundación BBVA, FEDER [European Regional Development Fund, EU]; the Fundación Científica Asociación Española Contra el Cáncer (IDEAS175CARR; GCTRA18006CARR, with M. Graupera and R.R. Gomis), "La Caixa" Foundation (HR17-00094), and the European Research Council (Starting Grant , PoC , and Consolidator Grant 819242). G. Velasco's research is funded by Fundació la Marató de TV3 (20134031). R.R. Gomis is supported by "La Caixa" Foundation (HR17-00092). CIBERONC was cofunded with European Regional Development funds and funded by Instituto de Salud Carlos III. L. Valcarcel-Jimenez was funded by a Basque Government predoctoral grant. |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra, i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Published in: | The journal of experimental medicine, Vol. 217 (march 2020) , ISSN 1540-9538 |
