Data from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models

<div><p>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.</p><p>We show here that prostate epithelial cell–specific expression of a mutant form of Plexin-B1 (<i>P1597L</i>) 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 (<i>PbCre⁺Pten^fl^/flKras^G12V</i>and <i>PbCre⁺Pten^fl^/flp53^fl/^fl</i>). In contrast, prostate epithelial cell–specific expression of wild-type (WT) Plexin-B1 in <i>PbCre⁺Pten^fl^/flKras^G12V</i> mice significantly decreases metastasis, showing that a single clinically relevant <i>Pro1597Leu</i> amino-acid change converts Plexin-B1 from a metastasis-suppressor to a metastasis-promoter. Furthermore, <i>PLXNB1^P1597L</i> significantly increased invasion of tumor cells into the prostate stroma, while <i>PLXNB1^WT</i>reduced invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Deletion of RhoA/C or PDZRhoGEF in <i>Pten^fl^/flKras^G12VPLXNB1^P1597L</i> mice suppressed metastasis, implicating the Rho/ROCK pathway in this phenotypic switch<i>.</i> Germline deletion of Plexin-B1, to model anti-Plexin-B1 therapy, significantly decreased invasion and metastasis in both models.</p><p>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.</p>Significance:<p>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 <i>P1597L</i> mutant, is such a target.</p></div>