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author Hermanova, Ivana
Zúñiga-García, Patricia
Caro-Maldonado, Alfredo
Fernandez-Ruiz, Sonia
Salvador, Fernando
Martín-Martín, Natalia
Zabala-Letona, Amaia
Nuñez-Olle, Marc
Torrano, Verónica
Camacho, Laura
Lizcano, Jose M.
Talamillo, Ana
Carreira, Suzanne
Gurel, Bora
Cortazar, Ana R.
Guiu, Marc
López, Jose I.
Martinez-Romero, Anabel
Astobiza, Ianire
Valcarcel-Jimenez, Lorea
Lorente, Mar
Arruabarrena-Aristorena, Amaia
Velasco, Guillermo
Gomez-Muñoz, Antonio
Suárez-Cabrera, Cristian
Lodewijk, Iris
Flores, Juana M.
Sutherland, James D.
Barrio, Rosa
de Bono, Johann S.
Paramio, Jesús M.
Trka, Jan
Graupera, Mariona
Gomis, Roger R.
Carracedo, Arkaitz
author_facet Hermanova, Ivana
Zúñiga-García, Patricia
Caro-Maldonado, Alfredo
Fernandez-Ruiz, Sonia
Salvador, Fernando
Martín-Martín, Natalia
Zabala-Letona, Amaia
Nuñez-Olle, Marc
Torrano, Verónica
Camacho, Laura
Lizcano, Jose M.
Talamillo, Ana
Carreira, Suzanne
Gurel, Bora
Cortazar, Ana R.
Guiu, Marc
López, Jose I.
Martinez-Romero, Anabel
Astobiza, Ianire
Valcarcel-Jimenez, Lorea
Lorente, Mar
Arruabarrena-Aristorena, Amaia
Velasco, Guillermo
Gomez-Muñoz, Antonio
Suárez-Cabrera, Cristian
Lodewijk, Iris
Flores, Juana M.
Sutherland, James D.
Barrio, Rosa
de Bono, Johann S.
Paramio, Jesús M.
Trka, Jan
Graupera, Mariona
Gomis, Roger R.
Carracedo, Arkaitz
author_sort Hermanova, Ivana
collection PubMed
description 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.
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spelling pubmed-79711412021-03-26 Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer Hermanova, Ivana Zúñiga-García, Patricia Caro-Maldonado, Alfredo Fernandez-Ruiz, Sonia Salvador, Fernando Martín-Martín, Natalia Zabala-Letona, Amaia Nuñez-Olle, Marc Torrano, Verónica Camacho, Laura Lizcano, Jose M. Talamillo, Ana Carreira, Suzanne Gurel, Bora Cortazar, Ana R. Guiu, Marc López, Jose I. Martinez-Romero, Anabel Astobiza, Ianire Valcarcel-Jimenez, Lorea Lorente, Mar Arruabarrena-Aristorena, Amaia Velasco, Guillermo Gomez-Muñoz, Antonio Suárez-Cabrera, Cristian Lodewijk, Iris Flores, Juana M. Sutherland, James D. Barrio, Rosa de Bono, Johann S. Paramio, Jesús M. Trka, Jan Graupera, Mariona Gomis, Roger R. Carracedo, Arkaitz J Exp Med Brief Definitive Report 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. Rockefeller University Press 2020-03-27 /pmc/articles/PMC7971141/ /pubmed/32219437 http://dx.doi.org/10.1084/jem.20191787 Text en © 2020 Hermanova et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Brief Definitive Report
Hermanova, Ivana
Zúñiga-García, Patricia
Caro-Maldonado, Alfredo
Fernandez-Ruiz, Sonia
Salvador, Fernando
Martín-Martín, Natalia
Zabala-Letona, Amaia
Nuñez-Olle, Marc
Torrano, Verónica
Camacho, Laura
Lizcano, Jose M.
Talamillo, Ana
Carreira, Suzanne
Gurel, Bora
Cortazar, Ana R.
Guiu, Marc
López, Jose I.
Martinez-Romero, Anabel
Astobiza, Ianire
Valcarcel-Jimenez, Lorea
Lorente, Mar
Arruabarrena-Aristorena, Amaia
Velasco, Guillermo
Gomez-Muñoz, Antonio
Suárez-Cabrera, Cristian
Lodewijk, Iris
Flores, Juana M.
Sutherland, James D.
Barrio, Rosa
de Bono, Johann S.
Paramio, Jesús M.
Trka, Jan
Graupera, Mariona
Gomis, Roger R.
Carracedo, Arkaitz
Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
title Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
title_full Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
title_fullStr Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
title_full_unstemmed Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
title_short Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
title_sort genetic manipulation of lkb1 elicits lethal metastatic prostate cancer
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971141/
https://www.ncbi.nlm.nih.gov/pubmed/32219437
http://dx.doi.org/10.1084/jem.20191787
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