About the Project
Background. Cellular senescence is a state of cell cycle arrest which may arise in response to a number of stimuli, including oncogene activity and telomere attrition. In the early stages of cancer development, senescence is protective, but there is evidence that the development and persistence of senescence in tumour cells and the microenvironment can contribute to resistance to anticancer therapies (https://doi.org/10.1016/j.trecan.2020.05.004). Head and neck cancer (HNC) incidence is increasing with significant treatment challenges, as recurrence is common and prognosis poor. Cisplatin, the mainstay of HNC chemotherapy, has well-described senescence-inducing effects and senescence has been implicated in immunotherapy resistance (https://doi.org/10.1172/JCI133679).
Objectives: To generate a comprehensive overview of the role that senescence plays in determining the response to oncological therapy in HNC. Specifically:
1. describe the extent of senescence in primary and recurrent HNCs, in the tumour and in fibroblast and lymphocytes in the microenvironment.
2. model the effects of senescence in the tumour microenvironment on the ability of naïve and therapy-resistant HNC cells to grow, migrate and invade.
1. Assessment of fresh HNC tissues, (treatment naïve and treated recurrences - cisplatin and immunotherapy). Tumours will be disrupted and cells sorted by flow cytometry to identify lineages in which senescence can be investigated by cell cycle and other senescence-associated phenotype features, e.g. CD8+/CD28+ andCD8+/CD28- lymphocytes. These populations will be cross referenced to our existing single cell RNA Seq data.
2. A cohort of HNC tissues with known clinical outcomes. Various combinations of senescence-associated markers identified in 1 will be assessed in a large clinical cohort, both untreated and recurrent tumours.
3. Co-culture strategies, using cisplatin sensitive/resistant HNC cells, to assess if HNC cells and those derived in (1) can induce senescence and other effects (proliferation, migration etc) in treatment naïve tumour cells, fibroblasts and lymphocytes.
This project is clinically focussed, with significant potential for clinical translation, thus provides training in interdisciplinary skills and whole organism physiology. The project will be based in a clinical academic environment (primary and second supervisor) with focus on gaining skills in translational science and medicine with opportunity to evaluate the features of senescent cells in a growing single cell dataset the investigators are building in HNC. Equipping researchers to work in a both a fundamental science and clinical environment will be key in the research literacy of the workforce, and to drive clinical translation.
For further details of the project supervisors please see:
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 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, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
Studentships commence: 1st October 2021
Sven E Niklander, Hannah L Crane, Lav Darda, Daniel W Lambert, Keith D Hunter. The role of icIL-1RA type 1 in oral keratinocyte senescence and the development of the senescence associated secretory phenotype. bioRxiv 2020.07.06.189019; doi: https://doi.org/10.1101/2020.07.06.189019
Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, Hunt S, Catto JWF, Coletta RD, Mellone M, Thomas GJ, Parkinson EK, Prime SS, Paterson IC, Buttle DJ & Lambert DW (2018) A miRNA-145/TGF-β1 Negative Feedback Loop Regulates the Cancer-Associated Fibroblast Phenotype. Carcinogenesis. 39(6), 798-807. doi:10.1093/carcin/bgy032
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