Projects
The Cancer Systems Microscopy Lab is engaged in key projects including diagnostic analysis of cancer patient-derived circulating tumour cell samples, development of new strategies for therapeutic lead / drug discovery, fundamental research into the composition, regulation and function of recently discovered Reticular Adhesions, and Proteomic Microscopy-based analysis of cell signalling systems.
Multiplexed cell analysis based on liquid biopsy for safe, longitudinal precision diagnostics
We aim to enable precision medicine by revolutionising analysis of signals driving cancer progression and therapy-resistance. We sample circulating tumour cells (CTCs) longitudinally and analyse them using Proteomic Microscopy, imaging up to 50 markers per CTC to quantify activity across multiple resistance-linked signalling pathways. Using multivariate statistics and artificial intelligence (AI), we classify resistant cancers by their signalling-drivers and train models to predict resistance mechanisms. This defines biomarker signatures with potential to stratify patients for targeted therapies. Beginning with prostate cancer, this precision diagnostic strategy is generalisable to many cancers.
Recent funding from the Tour de Cure Foundation was accompanied by a video explaining part of our approach to precision diagnostics development using liquid biopsy and systems microscopy:
Unbiased drug discovery for targeted therapy development
We have developed and tested a new strategy for drug lead-discovery that incorporates phenotypic screening of large-scale drug libraries (> 100, 000 compounds to-date) via high-throughput imaging, quantitative image analysis and multivariate statistical data analysis / machine learning to identify structurally and mechanistically diverse compounds with desirable biological effects. Already employed to explore the phenotypic plasticity of the actin cytoskeleton and at the same time identify new actin-regulating compounds, we are now working to generalise this approach in order to accelerate the discovery of lead compounds as part of the drug development pipeline.
Single-cell and subcellular analysis of acute signalling dependence on pre-existing cell states
Through sequential immunofluorescence multiplexing of subcellular signalling and cell state markers, we aim to understand the soureces of heterogeneity in signalling within individual cells and across cell populations. In particular, we aim to understand how pre-existing cell states may modulate acute cell signalling responses to incident ligand signals. This will help to understand the sources of heterogeneity in cell signalling responses and the degree to which these are based on stochastic noise versus pre-determined differences in signal perception and processing.
Mapping Cell State dynamics in the Epithelial / Mesenchymal spectrum
We aim to understand the dynamics and heterogeneity in epithelial to mesenchymal transition (EMT) induced by a variety of stimuli, such as TGF-b. In paticular, we are investigating the roles of cell state plasticity and proliferative control in this process, to understand how these factors contribute to EMT and therefore tumour progression, metastasis and therapy resistance. Using multiplexed single cell imaging and clonal tracing, we hope to provide a new level of resolution on this highly studied yet still poorly understood process.