PhD Studentship (Martin Bushell)
Application closing date
All tuition fees will be paid.
Determining why the oncogenic gene expression programme requires the RNA helicase eIF4A1 in cancer cells.
Decades of research have focused on the role of oncogenes such as c-Myc which through their role as transcription factors allow the creation of an oncogenic mRNA repertoire which results in the devastating consequences. However, recent work from our lab and others have shown that the oncogenic mRNA landscape is equally dependent upon mRNA turnover, and that these processes are critically intertwined with the act of mRNA translation. Two major interrelated protein complexes, called the eIF4F (which contains eIF4A1) and Ccr4-Not complexes, orchestrate post-transcriptional events through opposing functions upon the mRNA lifecycle. Over the five years we have uncovered that these processes are dysregulated in human malignancies and when they are disrupted in mouse models of cancer, using either genetic or pharmacological approaches, the oncogenic mRNA landscape is unable to be maintained. Determination of the mechanistic details is now critical to define the optimal way through which these processes can be disrupted for the full realisation of the therapeutic potential of these powerful observations.
Research aims and methods.
In mouse colorectal cancer (CRC) models driven by APC deletion combined with expression of a mutant KRAS allele, the genetic removal of eIF4A1 inhibits tumour development and prolongs survival. All tumours that do develop arise from escaper cells which still express eIF4A1, demonstrating the essential role of eIF4A1 in tumorigenesis. Strikingly, the removal of eIF4A1 in these CRC models eliminates the c-Myc driven oncogenic transcriptomic signature. In contrast, in the wild-type mouse eIF4A1 is not required for either the normal expression of these c-Myc driven genes or the basal proliferation rates. We will use a collection of in vivo and in vitro model systems of CRC to determine how the removal of eIF4A1 activity via either genetic ablation or pharmacologically results in the collapse of the oncogenic transcriptomic and translational environment, establishing the relationship between cause and effect. To address this the student will use a combination of advanced next generation sequencing approaches including ribosome profiling and determination of mRNA half-life genome-wide coupled with bioinformatics and machine learning tools. This will allow us to understand why eIF4A1 is so critical for supporting the oncogenic mRNA landscape within cancer cells.
For informal enquiries, please email Prof Martin Bushell ([email protected]).