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How is the immune system alerted to DNA damage in skin cancer cells?


Project Description

The immune system helps protect us from cancer - a process called immunosurveillance. However, the interplay between the immune system and cancer cells is so far incompletely understood. We have recently discovered that keratinocytes in the skin alert the immune system when their DNA is damaged, by activating innate immune signalling cascades that lead to the production of cytokines and chemokines (Dunphy et al., 2018, Mol Cell, doi: 10.1016/j.molcel.2018.07.034). As pre-cancerous cells and early stage tumours often display hallmarks of persistent DNA damage and replication stress, the damage-activated innate immune response may provide an important signal for the elimination of potentially cancerous cells by the immune system.

The overall aim of this project is to define how damaged keratinocytes and skin cancer cells influence the immune response in their micro-environment. For this, you will culture human keratinocytes and cells derived from non-melanoma skin cancer, and measure their innate immune response after UV light-induced DNA damage. This will involve tracking the activation of signalling factors by Western blotting and confocal microscopy, and measuring the production of cytokines and chemokines using real-time PCR and ELISA. By making use of CRISPR gene targeting, siRNA and inhibitors, you will test which pattern recognition receptors and signalling factors mediate this response. We are particularly interested in the DNA sensors cGAS and IFI16, and their adaptor protein STING, which can detect cytosolic DNA after infection and injury, as well as damaged DNA in the nucleus (see Dunphy et al., Mol Cell 2018; Almine et al., Nature Comms 2017). You will also employ flow cytometry and cell migration assays to investigate the consequences of cytokine and chemokine release by keratinocytes on the recruitment and activation of innate and adaptive immune cells. By comparing normal human keratinocytes to cells derived from cutaneous squamous cell carcinoma, we will test whether the DNA damage-induced innate immune signaling pathways are lost during tumour development, potentially mediating immune evasion of the tumour. This may provide important clues for the discovery of novel drug targets for the treatment of non-melanoma skin cancer, which is common in the UK, and increasing in incidence.

This project is a collaboration between the Unterholzner and Jackson-Jones laboratories based within the Division of Biomedical and Life Sciences at Lancaster University; the division offers a friendly research environment that strongly supports the individual needs of team members and actively promotes a healthy work-life balance. The Faculty of Health and Medicine is committed to family-friendly and flexible working policies and has held a Silver Athena SWAN award since 2014 in recognition of its good employment practice undertaken to address gender equality in higher education and research.

This project would suit a motivated candidate with an interest in cell signalling, immunology and cancer. Some research experience employing cell culture, molecular biology and immunology techniques would be an advantage.

For more information please contact Dr Leonie Unterholzner () or Dr Lucy Jackson-Jones ().

Applications are made by completing an application for PhD Biomedical and Life Sciences October 2019 through our online application system. Closing date: midnight 15th April 2019

Links:
http://www.lancaster.ac.uk/fhm/about-us/people/leonie-unterholzner
http://www.lancaster.ac.uk/fhm/about-us/people/lucy-jackson-jones

Funding Notes

The project is fully funded by North West Cancer Research, with a start date in October 2019. The 3 year studentship includes a tax-free stipend of £19,000 per annum, university tuition fees (UK/EU rate), travel and research funds. Applicants must have (or be predicted to obtain) the equivalent of a first or upper second class degree in a relevant subject. Only UK and EU citizens are eligible to apply.

References

Dunphy G, Flannery SM, Almine JF, Connolly DJ, Paulus C, Jønsson KL, Jakobsen MR, Nevels MM, Bowie AG and Unterholzner L (2018). Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-B signalling after nuclear DNA damage. Molecular Cell, 71(5):745-760. https://doi.org/10.1016/j.molcel.2018.07.034

Almine JF, O'Hare CAJ, Dunphy G, Haga IR, Naik RJ, Atrih A, Connolly DJ, Taylor J, Kelsall IR, Bowie AG, Beard PM and Unterholzner L (2017). IFI16 and cGAS co-operate in the activation of STING during DNA sensing in human keratinocytes. Nature Communications, 8:14392. https://doi.org/10.1038/ncomms14392

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