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Using genetically encoded biosensors to investigate how UV exposure modulates the cell and cilia cycles in melanoma


Project Description

Malignant melanoma (MM) incidence has increased markedly over the last four decades, a consequence of changing attitudes towards tanning. Although much is known about the genetic changes apparent at MM diagnosis, comparatively little is known about early changes in melanocyte behaviour on UV-exposure that ultimately result in cancer. We know that loss of the primary cilium is linked to melanoma and that UV stress can modulate cilia assembly. This project will address how UV-exposure modulates the cell and cilia cycles in melanocytes. UV exposure can result in (1) cells pausing in the cycling compartment to repair their DNA damage, (2) cells moving to a quiescent compartment or (3) cells moving to an apoptotic compartment. We have recently shown in mice that adult differentiated melanocytes exist in cycling as well as quiescent compartments and that we can track cilia assembly in these compartments. This project will map in detail how melanocytes modulate their cell and cilia cycles and transition between 1, 2 and 3 in response to UV.

Genetically encoded biosensors exist to probe compartments (1-3) in vivo, including our recently published cell cycle and cilia reporter mouse, but there are no available melanocyte or keratinocyte cell lines that express them for in vitro assays. In order to test, at the individual cell level, the effects of UV exposure on the cell and cilia cycles this project will:

1. Develop new melanocyte and keratinocyte cell lines as in vitro models
2. Investigate individual cell heterogeneity in cell and cilia cycle characteristics including the movement between (1) quiescent -> (2) cycling -> (3) apoptotic compartments in vitro and in vivo
3. Understand how the cell cycle and the transition between these compartments is modulated by UV exposure in vitro and in vivo

By using live imaging to gather individual cell level data we will determine the outcomes of UV irradiation on individual cells and investigate whether they occur through direct UV exposure or through a bystander effect of UV-exposed keratinocytes.

The student will be joining a dynamic team that includes a North West Cancer Research funded postdoctoral fellow working on a closely related project.

Sarah Allinson: https://www.lancaster.ac.uk/bls/people/sarah-allinson
Richard Mort: https://www.lancaster.ac.uk/bls/people/richard-mort

Impact
In the UK ~15,400 people are diagnosed annually with melanoma; its incidence has increased 50% in 10 years. Historically melanoma incidence has been highest in Southern England. However, alarmingly, in the North West a reversal of this trend has been observed in young women (aged 10-29) and this has been attributed to increased use of sunbeds - 9/10 of which exceed safety rules. We still don’t understand why some melanocytes develop into melanoma and others don’t therefore we need better methods of examining the individual cell behaviour of these essential cells and their response to UV.

Feel free to contact any member of the supervisory team by email at ; or for further details about the project.

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

Funding Notes

Awards are available for UK or EU students only for a maximum of three years full-time study. Awards will cover University Tuition Fees and stipend at Research Council Doctoral Stipend Level (2018-2019: £14,777).

References

Ford MJ, Yeyati PL, Mali GR, Keighren MA, Waddell SH, Mjoseng HK, Douglas AT, Hall EA, Sakaue-Sawano A, Miyawaki A, Meehan RR, Boulter L, Jackson IJ, Mill P, Mort RL. A Cell/Cilia Cycle Biosensor for Single-Cell Kinetics Reveals Persistence of Cilia after G1/S Transition Is a General Property in Cells and Mice. Dev Cell. 2018 Nov 19;47(4):509-523.e5.

Mort, RL., Ross, RJH., Hainey, KJ., Harrison, OJ., Keighren, MA., Landini, G., Baker, RE., Painter, KJ., Jackson, IJ., and Yates, CA. (2016) 'Reconciling diverse mammalian pigmentation patterns with a fundamental mathematical model' Nat Commun. Jan 6;7:10288.

Mort, RL, Patton, E and Jackson, I. J. (2015). 'The Melanocyte Lineage in Development and Disease' Development. 15;142(4):620-632.

Glover, JD, Knolle, S, Wells, KL, Liu, D, Jackson, IJ, Mort, RL. and Headon, DK. (2015) 'Autonomous Maintenance of Differentiated and Undifferentiated Melanocyte Populations in Interfollicular Epidermis' Pigment cell & melanoma research, vol 28, no. 4, pp. 476-80.

How good is research at Lancaster University in Allied Health Professions, Dentistry, Nursing and Pharmacy?

FTE Category A staff submitted: 64.40

Research output data provided by the Research Excellence Framework (REF)

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