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oai:docta.ucm.es:20.500.14352/65592024-09-27T17:13:38Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Hermanova, Ivana author Zuñiga-García, Patricia author Caro-Maldonado, Alfredo author Fernández Ruiz, Sonia author Salvador, Fernando author Martín-Martín, Natalia author Zabala-Letona, Amaia author Nuñez-Olle, Marc author Torrano, Verónica author Camacho, Laura author Lizcano, José M. author Talamillo, Ana author Carreira, Suzanne author Gure, Bora author Cortazar, Ana R. author Guiu, Marc author López, José I. author Martinez-Romero, Anabel author Astobiza, Ianire author Valcarcel-Jimenez, Lorea author Lorente Pérez, María Del Mar author Arruabarrena-Aristorena, Amaia author Velasco Díez, Guillermo author Gomez-Muñoz, Antonio author Suarez-Cabrera, Cristian author Lodewijk, Iris author Flores Landeira, Juana María author Sutherland, James D. author Barrio, Rosa author De Bono, Johann S. author Paramio, Jesús M. author Trka, Jan author Graupera, Mariona author Gomis, Roger R. author Carracedo, Arkaitz author 2020-03-27 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. 0022-0949, ESSN 1477-9145 10.1084/jem.20191787 https://hdl.handle.net/20.500.14352/6559 https://rupress.org/jem/article/217/6/e20191787/151590/Genetic-manipulation-of-LKB1-elicits-lethal Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer