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 prostate cancer patients, significantly increases metastasis, in particular metastasis to distant sites, in two transgenic mouse models of prostate cancer (PbCre+Ptenfl/flKrasG12Vand PbCre+Ptenfl/flp53fl/fl). In contrast, prostate epithelial cell-specific expression of wild-type Plexin-B1 in PbCre+Ptenfl/flKrasG12V 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, PLXNB1P1597Lsignificantly increased invasion of tumour cells into the prostate stroma, while PLXNB1WTreduced invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Deletion of RhoA/C or PDZRhoGEF in Ptenfl/flKrasG12VPLXNB1P1597Lmice 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.

Objective: To develop a simulation model to identify key bottlenecks in the bladder cancer pathway at Royal Cornwall Hospital and predict the impact of potential changes to reduce these delays. Materials and methods: The diagnosis and treatment of muscle-invasive bladder cancer can suffer numerous delays, which can significantly affect patient outcomes. We developed a discrete event computer simulation model of the flow of patients through the bladder cancer pathway at the hospital, using anonymised patient records from 2014 and 2015. The changes tested in the model were for patients suspected to have muscle-invasive disease on flexible cystoscopy. Those patients were 'fast-tracked' to receive their transurethral resection of bladder tumour (TURBT) treatment using operating slots kept free for these patients. A staging computed tomography scan was booked in the haematuria clinic. Pathology requests were marked as 48 hour turnaround. The nurse specialist would then speak to the patient whilst they were on the ward following their TURBT to give information about their ongoing treatment and provide support. Results: The model predicted that if the changes were implemented, delays in the system could be reduced by around 5 weeks. The changes were implemented, and analysis of 3 months of the data post-implementation shows that the average time in the system was reduced by 5 weeks. The environment created by the changes in the pathway improved referral to treatment times in both muscle-invasive and non-muscle-invasive groups. Conclusion: The simulation model proved an invaluable tool for facilitating the implementation of changes. Simple changes to the pathway led to significant reductions in delays for bladder cancer patients at Royal Cornwall Hospital. Level of evidence: Not applicable for this cohort study.

<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>

<p>Metastatic deposits in Ptenfl/flp53fl/flPLXNB1P1597L mice</p>