UCL Prostate Cancer Research Centre
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Research Group Leader: Dr Magali Williamson
Metastatic prostate cancer is essentially incurable and is a leading cause of cancer-related death in men. The overall goal of the group is to identify the genetic changes that govern prostate cancer progression and to define the mechanisms involved, thereby finding new targets for anti-cancer therapy.
Semaphorins are a group of 20 or more secreted or membrane bound proteins that act as chemotactic cues for cells expressing their transmembrane receptors, plexins. Semaphorins have a role in the regulation of cell motility, invasion, adhesion and angiogenesis and have been implicated in cancer. We have identified 13 somatic missense mutations in the cytoplasmic domain of the gene for plexinB1, a semaphorin receptor, in prostate tumours. Mutations were found in 45% (40/88) of primary prostate cancers and 89% (8/9) of bone and 41% (7/17) lymph node metastases (Wong et al., PNAS 2007 104(48):19040-5). Overexpression of the protein also occurs in prostate cancer and some other cancers.
We have found that the mutations alter the function of the plexinB1 protein. The mutations inhibit binding of the small RhoGTPases Rac, Rnd, R-Ras and inhibit the R-RasGAP activity of plexinB1 but do not affect PDZRhoGEF binding or Rho activation or the interaction of plexinB1 with ErbB2 or Met. Cells expressing mutant forms of the protein exogenously show an increase in cell motility, invasion, adhesion and extension of lamellipodia relative to cells expressing the normal protein. Knockdown of expression of plexinB1 in prostate cancer cells affects cell motility and anchorage-independent growth.
The finding of functionally significant mutations in plexinB1 in prostate tumours and overexpression of the plexinB1 protein suggests that plexinB1 has a role in prostate cancer and so is a potential target for therapy. The next goals are to understand how plexinB1 contributes to prostate cancer progression and to design therapies to target this pathway.
Ongoing projects involve:
· The generation of transgenic models of prostate cancer
· The identification of inhibitors of plexinB1 signalling for use as potential therapies
· Investigation of the prognostic significance of plexinB1 mutations and protein expression to determine if these markers can be used to predict clinical outcome.
Page last modified on 24 jan 12 14:54