The complex process by which cancer cells invade local tissue and metastasise is responsible for approximately 90% of cancer related deaths. The cell biological events that underlie this transition to malignancy are driven by invariable alterations within the genome, however relatively little is known about the genetic determinants involved. If identified, novel genes which perturb the rate of tumour progression could become potential targets for future therapeutic intervention.
Using a novel in vivo system, it is possible to characterise the behaviour of transformed cells during the early stages of tumour development and follow these cells in real time, thus improving our understanding of the critical events that initiate cell proliferation, tumour cell invasion and metastasis. Using Drosophila as a model organism it is possible to generate neoplastic tumours within the dorsal thorax whereby clones of transformed cells are homozygous mutant for a specific tumour suppressor gene. By specifically labelling these transformed cells with GFP, their behaviour can be observed in high temporal and spatial resolution within the living epithelium. RNAi technology can also be employed to simultaneously knock-down expression of an additional gene specifically within the mutant tissue. This forms the basis of a large-scale screen for novel genes that may promote tumour progression in this epithelium.
So far we have screened through more than 400 genes, the majority of which have previously been implicated in cancer but remain uncharacterised. We have observed a wide range of phenotypes, with genes affecting cell proliferation, invasion, cell shape, actin organisation, junction integrity and epithelial multilayering. By setting ‘thresholds’ for particular phenotypes ‘hits’ have been identified which drastically enhance tumour progression, and these genes are in the process of being fully characterised to further our understanding of their role in tumour progression.