Understanding the causes and consequences of heterogeneous regulation of translation elongation in disease

Details

The interface between biochemistry and cell biology is a major scientific challenge; while we can dissect complex biological mechanisms in vitro, studying them in the context of a living cell is more difficult. This issue is even more challenging when we consider cell-to-cell heterogeneity. Methodological advances in studying biology at the single cell level have revealed heterogeneity within various model systems. To advance our knowledge of heterogeneity further, we need innovative technological advances to study molecular changes at the single cell level. We have recently shown that colorectal cancer cells exhibit unexpected molecular heterogeneity in the way they respond to some chemotherapies. This heterogeneity sees a subset of cells slowing their rates of translation elongation via an unknown signalling pathway. Translation elongation has not been previously analysed at the single cell level, in part due to a lack of tools to enable this. However, our observations provide evidence that this heterogeneity exists and could explain different response to chemotherapy. Importantly, we have also developed novel methods to analyse this heterogeneity in multiple model systems, including longitudinal analysis of living cells and within tissues from cancer patients.

This studentship will use models of colorectal cancer as a platform to investigate heterogeneous regulation of translation elongation. This will be directly relevant to colorectal cancer, where elongation rates are commonly upregulated, but also other cancers and disease states with elongation dysregulation. The student will determine how heterogeneity arises, what the consequences of heterogeneity are and explore how pervasive this phenomenon is. Our aim is to understand the drivers of heterogeneity and how their modulation could benefit disease management by altering the fate of specific subpopulations of cell. The project design and supervision provided during this studentship will allow the student to develop technical and transferable skills for their future careers.

Eligibility 

Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a subject related to biological sciences.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cancer sciences Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester

If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

References

Knight J, Vlahov N, Gay D, Ridgway R, Faller W, Proud C, Mallucci G, von der Haar T, Smales M, Willis A and Sansom O (2021). Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K. Elife. (doi.org/10.7554/eLife.69729).

In this paper, John Knight defined the requirement for fast translation elongation in colorectal cancer and identified a signature for this in human tissue. We also identified a way to suppress elongation that suppressed tumour proliferation.

Knight J, Alexandrou C, Skalka G, Vlahov N, Pennel K, Officer L, Teodosio A, Kanellos G, (28 authors), Bushell M and Sansom O (2021). MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression. Cancer Discovery. (doi:10.1158/2159-8290.CD-20-0652).

Here John Knight found consistently elevated rates of translation elongation in colorectal cancer models and a protective resistance mechanism driven by mutant KRAS that ensures rapid elongation is maintained.

Kershaw C, Nelson M, Lui J, Bates C, Jennings M, Hubbard S, Ashe M and Grant C (2021). Integrated multi-omics reveals common properties underlying stress granule and P-body formation. RNA Biology. (doi.org/10.1080/15476286.2021.1976986).

Here the Ashe group used ribosome profiling, among other biochemical and imaging analyses, to determine the effects of condensate formation on translation.

Kershaw C, Nelson M, Castelli L, Pavitt G, Hubbard S and Ashe M (2023). Translation factor and RNA binding protein mRNA interactomes support broader RNA regulons for posttranscriptional control. Journal of Biological Chemistry. (doi.org/10.1016/j.jbc.2023.105195).

This work from the Ashe group demonstrates the supervisory team’s expertise in the molecular analysis of protein synthesis, including data analysis from large omics experiments.

Coulson-Gilmer C, Morgan R, Nelson L, Barnes B, Tighe A, Wardenaar R, Spierings D, (4 authors) McGrail J, Taylor S (2021). Replication catastrophe is responsible for intrinsic PAR glycohydrolase inhibitor-sensitivity in patient-derived ovarian cancer models. Journal of Experimental & Clinical Cancer Research. (doi.org/10.1186/s13046-021-02124-0)

In this paper, the Taylor group utilised high-content imaging using phospho-protein biomarkers to characterise drug responses.