Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models

Metastatic prostate cancer is essentially incurable and is a leading cause of cancer-related morbidity and mortality in men, yet the underlying molecular mechanisms are poorly understood. Plexins are transmembrane receptors for semaphorins with divergent roles in many forms of cancer. We show here that prostate epithelial cell–specific expression of a mutant form of Plexin-B1 (P1597L) which was identified in metastatic deposits in patients with prostate cancer, significantly increases metastasis, in particular metastasis to distant sites, in two transgenic mouse models of prostate cancer (PbCre(+)Pten(fl)(/fl)Kras(G12V)and PbCre(+)Pten(fl)(/fl)p53(fl/)(fl)). In contrast, prostate epithelial cell–specific expression of wild-type (WT) Plexin-B1 in PbCre(+)Pten(fl)(/fl)Kras(G12V) mice significantly decreases metastasis, showing that a single clinically relevant Pro1597Leu amino-acid change converts Plexin-B1 from a metastasis-suppressor to a metastasis-promoter. Furthermore, PLXNB1(P1597L) significantly increased invasion of tumor cells into the prostate stroma, while PLXNB1(WT)reduced invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Deletion of RhoA/C or PDZRhoGEF in Pten(fl)(/fl)Kras(G12V)PLXNB1(P1597L) mice suppressed metastasis, implicating the Rho/ROCK pathway in this phenotypic switch. Germline deletion of Plexin-B1, to model anti-Plexin-B1 therapy, significantly decreased invasion and metastasis in both models. Our results demonstrate that Plexin-B1 plays a complex yet significant role in metastasis in mouse models of prostate cancer and is a potential therapeutic target to block the lethal spread of the disease. SIGNIFICANCE: Few therapeutic targets have been identified specifically for preventing locally invasive/oligometastatic prostate cancer from becoming more widely disseminated. Our findings suggest Plexin-B1 signaling, particularly from the clinically relevant P1597L mutant, is such a target.