Phospholipase Cγ as a Target for Therapy in Tumour Invasion and Angiogenesis

Tumour Biology and Metastasis Team

Section: Cancer Research UK Cancer Therapeutics Unit

(In collaboration with the Lipid Signalling Team, CBL and other teams in Cancer Therapeutics)

Phospholipase Cγ (PLCγ) is a key element in tumour cell motility and is also implicated in neoangiogenesis. We have found that it is critical not only for receptor tyrosine kinase-mediated chemotaxis, but also early, integrin-related changes leading to cell motility. Transient transfection of PLCγ1 siRNA significantly inhibits motility and chemotaxis of tumour cells and activated endothelial cells. Recently, stable and inducible transfectants of a highly metastatic prostate carcinoma have been successfully produced to explore effects of PLCγ1 knock down in vivo. Novel inhibitors of PLC have been identified in both a high throughput screen in collaboration with Wynne Aherne and a virtual screen run by Johannes Reynisson. Analogues synthesised by the Medicinal Chemistry Team are being evaluated in biochemical and cell functional assays including IP3 production, Ca²⁺ release and cell migration assays. Pharmacodynamic markers of PLC inhibition have been identified by microarray analysis and confirmed by RT-PCR and western blot. Further work will compare profiles of cells in which PLCγ1 has been inhibited by siRNA or pharmacological means with the aim of identifying markers of response and potential new invasion targets on this pathway.