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Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

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Hermanova, Ivana and Zuñiga-García, Patricia and Caro-Maldonado, Alfredo and Fernández Ruiz, Sonia and Salvador, Fernando and Martín-Martín, Natalia and Zabala-Letona, Amaia and Nuñez-Olle, Marc and Torrano, Verónica and Camacho, Laura and Lizcano, José M. and Talamillo, Ana and Carreira, Suzanne and Gure, Bora and Cortazar, Ana R. and Guiu, Marc and López, José I. and Martinez-Romero, Anabel and Astobiza, Ianire and Valcarcel-Jimenez, Lorea and Lorente Pérez, Mar and Arruabarrena-Aristorena, Amaia and Velasco Díez, Guillermo and Gomez-Muñoz, Antonio and Suarez-Cabrera, Cristian and Lodewijk, Iris and Flores Landeira, Juana M. and Sutherland, James D. and Barrio, Rosa and De Bono, Johann S. and Paramio, Jesús M. and Trka, Jan and Graupera, Mariona and Gomis, Roger R. and Carracedo, Arkaitz (2020) Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer. Journal of Experimental Biology, 217 (6). pp. 1-19. ISSN 0022-0949, ESSN 1477-9145

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Official URL: https://rupress.org/jem/article/217/6/e20191787/151590/Genetic-manipulation-of-LKB1-elicits-lethal



Abstract

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.


Item Type:Article
Uncontrolled Keywords:LKB1; Prostate cancer
Subjects:Medical sciences > Medicine > Medical genetics
Medical sciences > Medicine > Nephrology and Urology
Medical sciences > Medicine > Oncology
ID Code:62212
Deposited On:21 Sep 2020 09:51
Last Modified:27 Sep 2020 23:01

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