Research overview

Receptor Tyrosine Kinase (RTK) signalling can be a positive driving force for cell proliferation, survival and migration but it is kept under tight control via feedback loops. In cancer, these controls can be bypassed by a variety of mechanisms and we are investigating how this happens.

Our research group, based in Barts Cancer Institute, part of Queen Mary University of London, focuses on breast, pancreatic and endometrial cancer, using 2-D and 3-D cell-based models to investigate how cellular behaviour changes when RTK signalling is altered. We collaborate with clinical colleagues to determine the translational significance of our findings through analysis of patient samples.

Our current research aims:

1. Targeting oncogene addiction and drug resistance

Fibroblast Growth Factor Receptor (FGFR) mutations are key drivers of up to 20% of endometrial cancer and a number of cancers show dependency on oncogenic FGFR signaling, making FGFRs attractive targets for targeted therapies. We have used phosphoproteomics and gene expression analysis to dissect resistance pathways that are established in drug resistant cancer cells, to develop novel combination therapy approaches.

We have recently identified a new resistance pathway, mediated by PHLDA1 dependent regulation of Akt signalling, with implications for targeted therapies against both FGFRs and HER2. In an exciting new project, we are now adopting similar approaches to identify drug resistance mechanisms in glioblastoma.

2. Modelling breast cancer development in 3D culture

3D modelling fulfils a critical role in research, allowing for complex cell behaviour and interactions to be studied in physiomimetic conditions. We have used the Breast Cancer Now Tissue Bank, an invaluable resource of primary cells isolated directly from patients, to interrogate the interactions between myoepithelial and luminal cells in 3D using collagen gels.

Using lentiviral transduction of isolated cells, we have developed a model that allows us to study early events in breast cancer development, to help understand how breast cancer progresses, with the ultimate aim of improving early diagnosis and treatment.

3. Nuclear trafficking of FGFRs

We have discovered that, rather than signalling from the cell surface or within endosomes, FGFRs can be proteolytically cleaved following activation and that the cytoplasmic portion of the receptor can traffic to the nucleus and regulate gene transcription. We have identified this behaviour in invasive breast cancer cells both in vitro and in vivo.

Our goals are to dissect the mechanisms controlling proteolytic cleavage and trafficking and to identify the full range of target genes and identify novel putative targets to block the pro-invasive effects of nuclear FGFR signalling. We have shown that nuclear FGFR signalling is a critical mediator of cancer-stroma cross-talk in pancreatic cancer, and we are exploring the therapeutic potential of FGFR inhibition in blocking pancreatic cancer progression.

Members of The British Association for Cancer Research (BACR) & British Society for Cell Biology (BSCB)