Targeting dysregulated translational control in the tumour environment
Prof M Bushell
Dr J Le Quesne
No more applications being accepted
Funded PhD Project (European/UK Students Only)
The Medical Research Council Toxicology Unit is an internationally renowned institution focussed on the delivery of field-changing mechanistic insights into toxicology and disease. The Unit is equipped with state-of-the-art facilities and provides a supportive learning environment designed to meet the scientific and transferable skills required for an internationally competitive career.
The Toxicology Unit will be relocating to the University of Cambridge in 2020.
This Cancer Research UK funded studentship, is in collaboration with the CRUK Beatson Institute, is for 4 years commencing ASAP with an annual stipend of £19,000 (tax free). There is also the possibility of a one year post-doctoral position at the end of the studentship if required.
The student would be part of an intensive research program with many collaborators and experienced post-doctoral researchers all working towards defined aims of understanding how translational control dysregulation leads to cancer. This would be a supportive environment with cutting-edge methodologies allowing highly motivated individual to thrive and reach their potential.
Oncogenes are exquisitely dependent upon the eIF4F complex for their translation, which unwinds mRNA structure and facilitates ribosome recruitment. It acts as a signalling hub positioned at the end of several mitogenic pathways, and its upregulation is a common feature of malignancy and leads to drug resistance.
The effector component of the eIF4F complex is the RNA helicase eIF4A, and inhibition of this protein shows dramatic well-tolerated anticancer effects in animal models. eIF4A possesses two paralogues: the widely studied eIF4A1, and the highly similar eIF4A2, which are often assumed to be functionally redundant. However, our recent data show divergent functions and expression patterns of these two proteins. eIF4A1 is required for translation initiation and cellular proliferation; its expression defines proliferative regions within tissues and tumours, and predicts poor outcome in many cancers. eIF4A2 is expressed in mature differentiated and secretory cells and tumour stroma, induces growth arrest, and predicts good outcome.
eIF4F activity is critical for driving malignant gene expression programs in tumours, and any attempt to target eIF4F therapeutically will require in-depth mechanistic understanding of this
The main aims of the project will be:
1. To establish the mechanisms through which eIF4A paralogues sculpt the translational landscapes associated with proliferating and differentiated cells, especially within stromal and epithelial compartments of tumours.
2. To achieve selective disruption of eIF4A paralogues in mouse models of colon, pancreatic and lung cancers and their associated stromal fibroblasts, and to determine the effects of this on tumour growth, invasion and metastasis.
3. To determine whether eIF4F complex dysregulation is a universal underlying feature of human malignancy, how this occurs, and whether this helps to identify patient groups who are likely to benefit from particular anti-eIF4F strategies.
We will characterise the molecular roles of eIF4F/eIF4A in cancer and determine how they control intracellular and extracellular proteomes in both neoplastic cells and stroma. These studies will identify targetable vulnerabilities at the mechanistic heart of the cancer phenotype, and identify molecular targets and patient groups for clinical application.
Candidates must have qualifications at the level of a first-class or 2.1 Honours Degree in a biological science or related discipline.
Full funding is available for UK and EU applicants.
This student is available for immediate uptake and the advert will remain open until a suitable candidate is appointed.