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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Detalles Bibliográficos
Autores: 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, José Miguel, Talamillo, Ana, Carreira, Suzanne, Gurel, Bora, Cortazar, Ana Rosa, Guiu, Marc, López, Jose I., Martínez Romero, Anabel, Astobiza, Ianire, Valcarcel Jimenez, Lorea, Lorente, Mar, Arruabarrena-Aristorena, Amaia, Velasco, Guillermo, Gomez Muñoz, Antonio, Suarez Cabrera, Cristian, Lodewijk, Iris, Flores, Juana M., Sutherland, James D., Barrio, Rosa, Bono, Johann Sebastian de, Paramio, Jesús M., Trka, Jan, Graupera i Garcia-Milà, Mariona, Gomis i Cabré, Roger, Carracedo, Arkaitz
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/171752
Acceso en línea:https://hdl.handle.net/2445/171752
Access Level:acceso abierto
Palabra clave:Càncer de pròstata
Metàstasi
Prostate cancer
Metastasis
Descripción
Sumario: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 Lkbl 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(K781), 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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