Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models

Abstract

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.

B-type plexins regulate mitosis via RanGTPase

“…22 PlexinB1 is mutated in prostate cancer 50 and Prostate epithelial cell-specific overexpression of a mutant form of PlexinB1 in vivo promotes metastasis 51 Conversely loss of Plexinb1 is associated with poor prognosis in melanoma 52 and estrogen receptor–positive breast cancer. 51…”

“…20,47 For example, PlexinB1 overexpression is a bad prognostic factor in ErbB2-amplified breast cancer 48 and ovarian cancer 49 while Sema3C, a ligand for PlexinB1 is overexpressed in prostate cancer. 22 PlexinB1 is mutated in prostate cancer 50 and Prostate epithelial cell-specific overexpression of a mutant form of PlexinB1 in vivo promotes metastasis 51 Conversely loss of Plexinb1 is associated with poor prognosis in melanoma 52 and estrogen receptor-positive breast cancer. 51 Together these results show that defects in B-type plexins may contribute to cancer progression by inducing chromosomal instability.…”