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MRC DiMeN Doctoral Training Partnership: The intersection of mechanical signalling and the hypoxic response as a targetable signalling nexus in pancreatic cancer

Funding
Funded
Study mode
Full-time
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Subject area
Biological and Biomedical Sciences
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Overview

During the early stages of cancer, tumour-specific alterations in the stiffness of the surrounding extracellular matrix, ECM (stromal rigidity) and depletion of oxygen levels (hypoxia) occur. These two physiological changes activate potent signalling systems in cancer cells that enhance their rate of proliferation, survival and capacity to spread. This proposal, based on preliminary data from the supervisory teams, will look at a newly identified, direct link between the cell’s rigidity-sensing machinery (Talin) and the hypoxia-inducible signalling system in pancreatic ductal adenocarcinoma (PDACs).

About this opportunity

Much of cell signalling occurs at the adhesions cell’s makes with the ECM. The primary supervisor discovered that the central scaffold in adhesion complexes, the protein talin, is a complex mechanosensor, comprised of force-dependent domains that act like switches, opening/closing in response to tiny forces, integrating chemical and mechanical signals. The forces acting on talin come from motor proteins in cells which require energy to function. A big question in the field is what happens if oxygen levels are depleted and the motors fail?

Using multiomics approaches we have identified a direct link between HIFs (hypoxia Inducible Factors), oxygen sensing (prolyl-hydroxylases, PHDs) and talin. In this project, we will uncover the role(s) of the hypoxia-sensing machinery in mechanotransduction. We hypothesise that integration of rigidity- and oxygen-sensing at adhesion sites represents an unexplored signalling nexus that’s hijacked in cancer.

Objectives

  1. Characterise the talin-HIF1a interaction.
  2. Characterise the proline hydroxylation of talin and use proteomics to find changes in talin interactome as a result of this modification.
  3. Establish transcriptional changes in normoxic and hypoxic conditions when rigidity sensing and/or talin-HIF1a interaction is perturbed.
  4. Develop targeted mutations to disrupt each interaction and assess effects on pancreatic cancer cellular responses.

Novelty/Timeliness

The new preliminary data and collaboration mean we are uniquely placed to deliver novel insights into cellular mechanisms. We predict that understanding this convergence of signalling pathways will identify novel therapeutic strategies for targeting PDAC.

N.B. As talin is an essential component of the synapses in our brain and HIF1a an established regulator of neuronal function this project will also have a neuroscience angle. The new knowledge gained in this project will expand our understanding of mechanical signalling in the brain where the binary switches in talin control synaptic signalling and reveal how this computational machinery is protected against hypoxia.

Experimental Approach

The primary supervisor is an expert in characterising talin interactions/function biochemically, with the secondary and tertiary supervisors exploring these interactions in cells in normoxic/hypoxic conditions.

This project combines our expertise’s in biochemistry, cell biology of normoxic/hypoxic cells, proteomic/transcriptomic analysis of PDACs as oxygen-sensing is perturbed and using state-of-the-art probes to visualise these changes in cells in real time.

This multidisciplinary project, at the interface between mechanobiology and hypoxia research, will provide an excellent training experience for the student and enhance our knowledge of cancer biology.

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.

Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/

Further reading

1. Kang M, Otani Y, Guo Y, Yan J, Goult BT and Howe A. (2024) The focal adhesion protein talin is a mechanically-gated A-kinase anchoring protein (AKAP). PNAS 121(13):e2314947121 https://doi.org/10.1073/pnas.2314947121
2. Gallego-Paez LM, Edwards WJS, Chanduri M, Guo Y, Koorman T, Lee C-Y, Grexa N, Derksen P, Yan J, Schwartz MA, Mauer J and Goult BT (2023) TLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity. J. Cell Biol 222(5):e202209010 https://doi.org/10.1083/jcb.202209010
3. Barnett SFH and Goult BT (2022) The MeshCODE to scale—visualising synaptic binary information. Front. Cell. Neurosci. 16:1014629 https://doi.org/10.3389/fncel.2022.1014629
4. Gough RE, Jones MC, Zacharchenko T, Le S, Yu M, Jacquemet G, Muench SP, Yan J., Humphries JD, Jørgensen C, Humphries MJ and Goult BT. (2021) Talin mechanosensitivity is modulated by a direct interaction with cyclin dependent kinase-1. J Biol Chem 297(1):100837 https://doi.org/10.1016/j.jbc.2021.100837
5. Jiang H, Druker J, Wilson JW, Bensaddek D, Swedflow S and Lamond AI (2025) Systematic characterization of site-specific proline hydroxylation using hydrophilic interaction chromatography and mass spectrometry eLife14:RP108128 https://doi.org/10.7554/eLife.108128.1
6. Batie M, Frost J, Frost M, Wilson JW, Schofield P and Rocha S (2019) Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363,1222-1226(2019). https://doi.org/10.1126/science.aau5870
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Who is this for?

Applicants for postgraduate research study at Liverpool are normally expected to hold a UK first degree with a First Class or Upper Second Class degree classification, or a Second Class degree plus a Master’s degree. Equivalent international qualifications are also accepted, and their equivalence will be evaluated on the basis of the information provided by the European Network of Information Centres (ENIC) formerly NARIC as well as internal guidance based on our experience of a qualification’s suitability as a preparation for our programmes.

For applicants whose first language is not English, an IELTS score of 6.5 with no band score lower than 5.5, or an equivalent University of Liverpool acceptable English language qualification. For further details and other acceptable English language qualifications please see here: http://www.liv.ac.uk/study/international/countries/english-language/

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How to apply

  1. 1. Contact supervisors

    Supervisors:

    • Prof Ben Goult
    • Prof S Rocha
    • Dr Brian Ortmann

  2. 2. Prepare your application documents

    All applications are made via the application form accessed on the DiMeN website at www.dimen.org.uk/ Please read the full application guidance on the website before submitting an application.

  3. 3. Apply

    Finally, register and apply online. You'll receive an email acknowledgment once you've submitted your application. We'll be in touch with further details about what happens next.

    You should only follow this step if you’ve successfully completed the DiMeN application process

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Funding your PhD

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£20,780 for 2024/25) and project costs. We have a very small number of funded studentships for exceptional international applicants. Please read additional guidance here: View Website

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Contact us

Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.

Prof Ben Goult
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