Research Interest

The role of heat shock protein chaperones in tumour invasion and metastasis

Sue Eccles, Cara Lomas (PhD studentship) in collaboration with Marissa Powers, Swee Sharp, Paul Workman

Molecular chaperones such as HSP90 are responsible for the correct folding and localization of several key signalling molecules involved in tumour cell proliferation, invasion and angiogenesis, including ERB-B2, AKT, BRAF, CRAF, MET, eNOS, VEGFR and HIF-1alpha. We have shown that 17AAG and our novel HSP90 inhibitor NVP-AUY922 potently inhibit not only tumour cell proliferation, but also angiogenesis, invasion and metastasis in vitro and in vivo.  

Recently, it has become evident from both clinical and laboratory studies that different chaperones may be implicated in progression of specific tumour types (such as HSP27 in prostate cancer, alpha-B crystallin in breast cancer). In addition, by virtue of their expression, ‘clientele’ or subcellular localization, individual chaperones may have specific functions in the cellular processes required for invasion and metastasis.

This project aims to profile chaperone protein expression in a panel of human tumour cell lines and metastatic variants that we have generated. Levels will be measured in 2D and 3D where microenvironmental stresses such as hypoxia may be expected to modify chaperone activity. Selected chaperones will then be stably or inducibly knocked down using shRNA in order to determine effects on 3D growth and invasion in vitro. Information obtained will be used to test the effects of isoform-selective inhibition strategies in in vivo metastasis models.