Abstract

My lab is interested in understanding the mechanisms that drive colorectal cancer initiation and progression with the aim of identifying novel therapeutic targets for its treatment. Recently published studies, and data generated in our lab, suggest dysregulated RNA splicing is an important driver of tumourigenesis. Using genetically engineered mouse models and organoid culture we are investigating whether RNA splicing may be a potential therapeutic target in colorectal cancer. So far we have been able to demonstrate that tumour organoid cells are highly susceptible to inhibition of RNA splicing. Interestingly, organoids derived from normal tissue are much more tolerant suggesting a possible ‘therapeutic window’ for RNA splicing inhibition. We have also shown that a key component of the RNA splicing machinery is critically important for promoting proliferation following tumour initiation in a genetically engineered mouse model of the disease. Deletion of this RNA splicing factor inhibits the acquisition of cancer stem cell properties via modulation of key RNA splicing events. Importantly, as RNA splicing is a core cellular process, resistance to its therapeutic targeting may be less likely to develop thus indicating RNA splicing inhibition may be a viable therapeutic option for colorectal cancer.