| Literature DB >> 32219437 |
Ivana Hermanova1, Patricia Zúñiga-García1, Alfredo Caro-Maldonado1, Sonia Fernandez-Ruiz1,2, Fernando Salvador2,3, Natalia Martín-Martín1,2, Amaia Zabala-Letona1,2, Marc Nuñez-Olle3, Verónica Torrano1,2,4, Laura Camacho1,4, Jose M Lizcano5, Ana Talamillo1, Suzanne Carreira6, Bora Gurel6, Ana R Cortazar1,2, Marc Guiu3, Jose I López7, Anabel Martinez-Romero2,8, Ianire Astobiza1,2, Lorea Valcarcel-Jimenez1, Mar Lorente9, Amaia Arruabarrena-Aristorena1, Guillermo Velasco9,10, Antonio Gomez-Muñoz4, Cristian Suárez-Cabrera11,12, Iris Lodewijk11,12, Juana M Flores13, James D Sutherland1, Rosa Barrio1, Johann S de Bono6,14, Jesús M Paramio2,11,12, Jan Trka15,16, Mariona Graupera2,8, Roger R Gomis2,3,17, Arkaitz Carracedo1,2,4,18.
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.Entities:
Year: 2020 PMID： 32219437 DOI： 10.1084/jem.20191787
Source DB: PubMed Journal: J Exp Med ISSN： 0022-1007 Impact factor: 14.307