A novel protease and growth factor regulated signalling system in ovarian cancer

In western countries ovarian cancer (OC) is the leading cause of gynaecologic cancer death. We will examine a novel molecular pathway in OC that is centred on CDCP1, a cell surface receptor. We have reported that CDCP1 protein expression is upregulated in the majority of ~500 examined patient tumours, and its blockade reduces cell migration and survival in vitro, and tumour growth and metastasis in mouse models. CDCP1 blockade also increases OC chemotherapy responses in in vitro and mouse models. We have also shown that CDCP1’s role in OC is accentuated by a growth factor signalling axis that is often activated in this cancer. The proposed research builds on these observations by characterising and modulating novel CDCP1 regulatory pathways that promote OC. We hypothesise that serine protease (SP) activity and growth factor (GF) signalling are required for CDCP1’s roles in OC, and that modulation of these mechanisms will improve the efficacy of agents that target CDCP1 in OC. We will address this using in vitro and mouse models of OC, as well as patient samples. We will determine how SPs and GFs promote CDCP1’s roles in OC, including how these regulate CDCP1’s release from and trafficking within cells. We will use a state of the art microscopy screening approach to identify the SPs that regulate CDCP1. We will then define the effect on OC of modulating these SPs. We will determine the impact that a function blocking antibody has on cellular trafficking of CDCP1, and also how this antibody binds to CDCP1 to block its role in OC. The project is significant because it delineates the components of a new pathway that is important and targetable in a commonly lethal female malignancy. It is innovative because we are the first to identify this new pathway, and will employ unique reagents and cutting edge approaches and models to delineate the pathway’s key features.