How does the tumour microenvironment drive therapeutic resistance?

Cancer cells can acquire stromal or developmental-like phenotypes allowing them to masquerade as other cell types, making the challenge of therapeutic targeting problematic. Gastric tumours are driven by cancer stem cells, positioning cancer stem cells as attractive therapeutic targets. While targeted ablation of cancer stem cells induces striking tumour regression, sadly these effects are short lived. Tumour cells with access to 'niche' factors are more likely to assume the role of cancer stem cells and propel tumour growth, which stresses a need to identify the molecular and cellular drivers of plasticity to inform drug discovery and improve patient outcome. Fibroblast cells secrete and express 'niche' factors that remodel the tumour landscape to promote growth, plasticity and escape cytotoxic effects of targeted therapy. Surprisingly, we do not understand how fibroblasts contribute to poor therapeutic outcomes during the evolution of stomach cancer, representing a significant knowledge gap. You will use state-of-the-art mouse models selectively ablate cancer stem cell populations from tumours to study the response of the surrounding tumour microenvironment to re-instate tumour growth ie. plasticity. The transcriptional profile of single-cells will be incorporated to identify the critical signalling pathways that drive tumour plasticity.