Dr Adrian Biddle
Dr Biddle is an NC3Rs Research Fellow in the Centre for Cell Biology and Cutaneous Research. His research interest is in non-genetic cellular heterogeneity in cancer, and how such heterogeneity might be responsible for therapeutic resistance. He is particularly interested in the plasticity of heterogeneous cancer cell sub-populations, the molecular mechanisms driving plasticity, and how plastic sub-populations can be modelled in vitro.
In vitro modelling of cancer stem cell therapeutic responses for drug discovery
Session: Developments within In Vitro Cancer Research
Author: Adrian Biddle, Blizard Institute, Queen Mary University of London, London, UK.
Abstract: The aim of our research is to develop human cell culture models that have demonstrable relevance to human cancer and can replace mouse cancer models to enable more efficient drug discovery. Using an oral cancer cell line model, we have demonstrated that cancer stem cells (CSCs) drive tumour metastasis by undergoing epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and mesenchymal sub-populations (Biddle et al., 2011). We have further demonstrated heightened therapeutic resistance and metastatic potential of a novel CSC sub-population in oral cancer that exhibits a hybrid epithelial-mesenchymal phenotype and has a CD44highEpCAMlowCD24+ cell surface marker profile (Biddle et al., 2016). This presents an attractive target for new therapies aimed at overcoming tumour therapeutic resistance and metastatic proclivity. We have now developed a method to enrich these CSCs in cell culture for therapeutic development (Biddle et al., 2016) and, using this method, we are able to test candidate therapeutic compounds and further dissect the molecular mechanisms driving the behaviour of these hybrid CSCs.
The demonstration that CSC sub-populations can be modelled using cell lines in vitro provides an opportunity for the efficient discovery of novel therapeutic strategies. However, there is currently some uncertainty over the relevance of cell culture models to human cancer, and this has driven an increase in the use of mouse cancer models. New models that possess greater physiological relevance whilst retaining the experimental tractability of in vitro models are therefore required. We are currently developing an in vitro 3D model system that can incorporate both human cancer cell lines and explanted fresh tumour material, and testing its ability to accurately model human tumour biology and therapeutic response. We are also building a validation model using FFPE tumour sections to comprehensively validate the findings from our human cell culture model.
References: Biddle, A., Liang, X., Gammon, L., Fazil, B., Harper, L. J., Emich, H., Costea, D. E., and Mackenzie, I. C. (2011). Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res 71, 5317-5326.
Biddle, A., Gammon, L., Liang, X., Costea, D. E., and Mackenzie, I. C. (2016). Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma. EBioMedicine 4, 138-145.