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, LKB1K78I, 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.

Biochemistry and Molecular Biology Department University of the Basque Country Bilbao Spain

Cancer Science Program Institute for Research in Biomedicine The Barcelona Institute of Science and Technology Barcelona Spain

Center for Cooperative Research in Biosciences Basque Research and Technology Alliance Derio Spain

Childhood Leukaemia Investigation Prague Czech Republic

CIBERONC Madrid Spain

Department of Animal Medicine and Surgery School of Veterinary Medicine Complutense University of Madrid Madrid Spain

Department of Biochemistry and Molecular Biology School of Biology Complutense University Madrid Spain

Department of Paediatric Haematology Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pathology Cruces University Hospital Biocruces Institute University of the Basque Country Barakaldo Spain

Grupo de Oncología Celular y Molecular Hospital Universitario 12 de Octubre Madrid Spain

Ikerbasque Basque Foundation for Science Bilbao Spain

Institució Catalana de Recerca i Estudis Avançats Barcelona Spain

Instituto de Investigaciones Sanitarias San Carlos Madrid Spain

Protein Kinases and Signal Transduction Laboratory Institut de Neurociències and Departament de Bioquímica i Biologia Molecular Universitat Autònoma de Barcelona Bellaterra Barcelona Spain

The Institute of Cancer Research London UK

The Royal Marsden National Health Service Foundation Trust London UK

Unidad de Oncología Molecular Centro de Investigaciones Energéticas Medioambientales y Tecnológicas Madrid Spain

Vascular Signalling Laboratory Program Against Cancer Therapeutic Resistance Institut d'Investigació Biomèdica de Bellvitge Barcelona Spain

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$a Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer / $c I. Hermanova, P. Zúñiga-García, A. Caro-Maldonado, S. Fernandez-Ruiz, F. Salvador, N. Martín-Martín, A. Zabala-Letona, M. Nuñez-Olle, V. Torrano, L. Camacho, JM. Lizcano, A. Talamillo, S. Carreira, B. Gurel, AR. Cortazar, M. Guiu, JI. López, A. Martinez-Romero, I. Astobiza, L. Valcarcel-Jimenez, M. Lorente, A. Arruabarrena-Aristorena, G. Velasco, A. Gomez-Muñoz, C. Suárez-Cabrera, I. Lodewijk, JM. Flores, JD. Sutherland, R. Barrio, JS. de Bono, JM. Paramio, J. Trka, M. Graupera, RR. Gomis, A. Carracedo

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$a 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, LKB1K78I, 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.

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