Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

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...

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Detalhes bibliográficos
Autores: Hermanova, Ivana, Zuñiga-García, Patricia, Caro-Maldonado, Alfredo, Fernández Ruiz, Sonia, Salvador, Fernando, Martín-Martín, Natalia, Zabala-Letona, Amaia, Nuñez-Olle, Marc, Torrano, Verónica, Camacho, Laura, Lizcano, José M., Talamillo, Ana, Carreira, Suzanne, Gure, Bora, Cortazar, Ana R., Guiu, Marc, López, José I., Martinez-Romero, Anabel, Astobiza, Ianire, Valcarcel-Jimenez, Lorea, Lorente Pérez, María Del Mar, Arruabarrena-Aristorena, Amaia, Velasco Díez, Guillermo, Gomez-Muñoz, Antonio, Suarez-Cabrera, Cristian, Lodewijk, Iris, Flores Landeira, Juana María, Sutherland, James D., Barrio, Rosa, De Bono, Johann S., Paramio, Jesús M., Trka, Jan, Graupera, Mariona, Gomis, Roger R., Carracedo, Arkaitz
Formato: artículo
Fecha de publicación:2020
País:España
Recursos:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/6559
Acesso em linha:https://hdl.handle.net/20.500.14352/6559
Access Level:acceso abierto
Palavra-chave:575:61
616.65-006
LKB1
Prostate cancer
Genética médica
Nefrología y urología
Oncología
2410.07 Genética Humana
3201.01 Oncología
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oai_identifier_str oai:docta.ucm.es:20.500.14352/6559
network_acronym_str ES
network_name_str España
repository_id_str
spelling Genetic manipulation of LKB1 elicits lethal metastatic prostate cancerHermanova, IvanaZuñiga-García, PatriciaCaro-Maldonado, AlfredoFernández Ruiz, SoniaSalvador, FernandoMartín-Martín, NataliaZabala-Letona, AmaiaNuñez-Olle, MarcTorrano, VerónicaCamacho, LauraLizcano, José M.Talamillo, AnaCarreira, SuzanneGure, BoraCortazar, Ana R.Guiu, MarcLópez, José I.Martinez-Romero, AnabelAstobiza, IanireValcarcel-Jimenez, LoreaLorente Pérez, María Del MarArruabarrena-Aristorena, AmaiaVelasco Díez, GuillermoGomez-Muñoz, AntonioSuarez-Cabrera, CristianLodewijk, IrisFlores Landeira, Juana MaríaSutherland, James D.Barrio, RosaDe Bono, Johann S.Paramio, Jesús M.Trka, JanGraupera, MarionaGomis, Roger R.Carracedo, Arkaitz575:61616.65-006LKB1Prostate cancerGenética médicaNefrología y urologíaOncología2410.07 Genética Humana3201.01 OncologíaGene 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.The Company of BiologistsUniversidad Complutense de Madrid20202020-03-2720202020-03-27journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/6559reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-CompartirIgual 3.0 Españahttps://creativecommons.org/licenses/by-nc-sa/3.0/es/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/65592026-06-02T12:44:21Z
dc.title.none.fl_str_mv Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
title Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
spellingShingle Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
Hermanova, Ivana
575:61
616.65-006
LKB1
Prostate cancer
Genética médica
Nefrología y urología
Oncología
2410.07 Genética Humana
3201.01 Oncología
title_short 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_sort Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer
dc.creator.none.fl_str_mv Hermanova, Ivana
Zuñiga-García, Patricia
Caro-Maldonado, Alfredo
Fernández Ruiz, Sonia
Salvador, Fernando
Martín-Martín, Natalia
Zabala-Letona, Amaia
Nuñez-Olle, Marc
Torrano, Verónica
Camacho, Laura
Lizcano, José M.
Talamillo, Ana
Carreira, Suzanne
Gure, Bora
Cortazar, Ana R.
Guiu, Marc
López, José I.
Martinez-Romero, Anabel
Astobiza, Ianire
Valcarcel-Jimenez, Lorea
Lorente Pérez, María Del Mar
Arruabarrena-Aristorena, Amaia
Velasco Díez, Guillermo
Gomez-Muñoz, Antonio
Suarez-Cabrera, Cristian
Lodewijk, Iris
Flores Landeira, Juana María
Sutherland, James D.
Barrio, Rosa
De Bono, Johann S.
Paramio, Jesús M.
Trka, Jan
Graupera, Mariona
Gomis, Roger R.
Carracedo, Arkaitz
author Hermanova, Ivana
author_facet Hermanova, Ivana
Zuñiga-García, Patricia
Caro-Maldonado, Alfredo
Fernández Ruiz, Sonia
Salvador, Fernando
Martín-Martín, Natalia
Zabala-Letona, Amaia
Nuñez-Olle, Marc
Torrano, Verónica
Camacho, Laura
Lizcano, José M.
Talamillo, Ana
Carreira, Suzanne
Gure, Bora
Cortazar, Ana R.
Guiu, Marc
López, José I.
Martinez-Romero, Anabel
Astobiza, Ianire
Valcarcel-Jimenez, Lorea
Lorente Pérez, María Del Mar
Arruabarrena-Aristorena, Amaia
Velasco Díez, Guillermo
Gomez-Muñoz, Antonio
Suarez-Cabrera, Cristian
Lodewijk, Iris
Flores Landeira, Juana María
Sutherland, James D.
Barrio, Rosa
De Bono, Johann S.
Paramio, Jesús M.
Trka, Jan
Graupera, Mariona
Gomis, Roger R.
Carracedo, Arkaitz
author_role author
author2 Zuñiga-García, Patricia
Caro-Maldonado, Alfredo
Fernández Ruiz, Sonia
Salvador, Fernando
Martín-Martín, Natalia
Zabala-Letona, Amaia
Nuñez-Olle, Marc
Torrano, Verónica
Camacho, Laura
Lizcano, José M.
Talamillo, Ana
Carreira, Suzanne
Gure, Bora
Cortazar, Ana R.
Guiu, Marc
López, José I.
Martinez-Romero, Anabel
Astobiza, Ianire
Valcarcel-Jimenez, Lorea
Lorente Pérez, María Del Mar
Arruabarrena-Aristorena, Amaia
Velasco Díez, Guillermo
Gomez-Muñoz, Antonio
Suarez-Cabrera, Cristian
Lodewijk, Iris
Flores Landeira, Juana María
Sutherland, James D.
Barrio, Rosa
De Bono, Johann S.
Paramio, Jesús M.
Trka, Jan
Graupera, Mariona
Gomis, Roger R.
Carracedo, Arkaitz
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 575:61
616.65-006
LKB1
Prostate cancer
Genética médica
Nefrología y urología
Oncología
2410.07 Genética Humana
3201.01 Oncología
topic 575:61
616.65-006
LKB1
Prostate cancer
Genética médica
Nefrología y urología
Oncología
2410.07 Genética Humana
3201.01 Oncología
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, 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-03-27
2020
2020-03-27
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/6559
url https://hdl.handle.net/20.500.14352/6559
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 3.0 España
https://creativecommons.org/licenses/by-nc-sa/3.0/es/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 3.0 España
https://creativecommons.org/licenses/by-nc-sa/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv The Company of Biologists
publisher.none.fl_str_mv The Company of Biologists
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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