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, 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
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/6559
Acceso en línea:https://hdl.handle.net/20.500.14352/6559
Access Level:acceso abierto
Palabra clave:575:61
616.65-006
LKB1
Prostate cancer
Genética médica
Nefrología y urología
Oncología
2410.07 Genética Humana
3201.01 Oncología
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 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.

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