| dc.description.abstract | Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate of all common solid tumours. Novel therapeutics strategies are necessary to significantly improve patient survival. Extracellular adenosine triphosphate (ATP) is elevated in PDAC and is associated with inflammation and immunosuppression. Consequently, the purinergic signalling axis is a promising target, as it includes several druggable membrane proteins, currently underexplored in PDAC. From all purinergic signalling targets, the ATP receptor P2Y2 had the strongest impact on overall survival, greatest association with hypoxia and highest cancer cell specific expression. Real-time migration and 3D sphere invasion assays revealed a crucial role for P2Y2 and its extracellular RGD motif in ATP-driven cancer migration and invasion. Using DNA-PAINT single-molecule super-resolution microscopy, the RGD motif in P2Y2 was shown to influence the number and distribution of P2Y2 and integrin αV molecules in the plasma membrane. Impairing the RGD motif function in P2Y2 also perturbed receptor internalisation, G protein and FAK/ERK signalling. Additionally, P2Y2 activation led to MET signalling, a strong driver of cancer cell migration. Bioinformatic analyses reinforced these results, with pancreatic cancers expressing high levels of P2Y2 showing a signature of MET-related cell motility. These findings reveal the potential of the P2Y2-integrin axis as an anti-metastatic target for PDAC. | en_US |
