Prostate Cancer Research Centre Metastasis Group
Our group investigates the molecular mechanisms behind cell invasion and metastasis in cancer. We are currently focussing on the semaphorin/plexin signalling pathway and its role in the spread of prostate cancer.
Our research is aimed at understanding how plexins regulate cell movement and cell signalling and so contributes to tumour progression, as a first step towards developing therapies to target PlexinB1 signalling in prostate cancer.
Our previous work has shown that PlexinB1, a cell surface receptor for semaphorin4D, is overexpressed and/or mutated in clinical prostate cancer, suggesting a role for PlexinB1 in prostate cancer progression (Figure 1).
PlexinB1 activates the tyrosine kinase receptor oncogenes ErbB2 and c-Met and regulates several small GTPases resulting in changes in the actin cytoskeleton and cell motility. Activation of PlexinB1 in prostate cancer cell lines in vitro increases cell migration, invasion and anchorage independent growth. Work on models of prostate cancer have shown that PlexinB1 acts as a metastasis-enhancing gene in prostate cancer and that blocking PlexinB1 function reduces metastasis.
We now also have evidence for a novel role of plexins in the nucleocytoplasmic trafficking of nuclear receptors, such as the androgen receptor, which may contribute to the development of castration-resistant prostate cancer (Figure 2). We are also investigating a role for plexins in spindle formation in mitosis (Figure 3).
Work is also underway to determine the prognostic significance of PlexinB1 expression levels in human prostate cancer.