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.
- MeSH
- epitel enzymologie patologie MeSH
- fosfohydroláza PTEN metabolismus MeSH
- HEK293 buňky MeSH
- heterozygot MeSH
- lidé MeSH
- metastázy nádorů MeSH
- mutantní proteiny metabolismus MeSH
- myši inbrední C57BL MeSH
- myši nahé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty enzymologie MeSH
- progrese nemoci MeSH
- prostata enzymologie patologie MeSH
- protein-serin-threoninkinasy nedostatek genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH