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(MRC DTP) Understanding how EDAR-signalling modulates susceptibility to skin and colorectal cancer


Project Description

This work will provide vital information to help stratify patients for EDAR-based therapy by determining the patient populations that are susceptible to oncogenic side-effects of these agents. It will also provide invaluable insight into the potential underlying mechanisms of cancer development in patient populations with high incidence of EDAR variants and thus reveal novel, future therapeutic targets.
EDAR is a cell-surface receptor that has pivotal roles during development. As well as being required developmentally, these pathways are frequently mutated in cancers, as alterations in these pathways enables cells to acquire many of the biological characteristics necessary to become cancerous. However, despite a clear link between the downstream pathways of EDAR signalling and cancer development, the specific role of EDAR signalling in cancer is poorly understood.
Our recent work has shown that over-activation of this pathway can drive breast and skin cancer development. These new findings; that EDAR-signalling is potentially cancer causing, are extremely important for two reasons; 1) several therapies are in development that stimulate EDAR signalling (e.g. for congenital deficiency in EDAR signalling), 2) East Asian and Native American groups have a high incidence of EDAR variants that cause over-activation of the pathway, which is potentially cancer-causing. Therefore there is a pressing need to 1) develop an effective way to model differential EDAR-signalling status to enable understanding of tumourigenesis in these discrete patient populations and 2) investigate the impact of EDAR signalling on tumour incidence and development in patients. These are the aims of this studentship.
Execution of this project involves collaboration with Shanghai Jiao Tong University School of Medicine (SJTUSM) and will employ a wide spectrum of research methods spanning in vitro molecular biology techniques to in vivo tumour modelling. This will provide the successful candidate with the breadth of knowledge and skills necessary for a successful future career in cancer research.

https://www.research.manchester.ac.uk/portal/K.G.Finegan.html
https://www.research.manchester.ac.uk/portal/keith.brennan.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Kowalczyk-Quintas, C. & Schneider, P. Ectodysplasin A (EDA) - EDA receptor signalling and its pharmacological modulation. Cytokine & growth factor reviews 25, 195-203 (2014).
2. Rakha, E.A. et al. Prognostic factors in metaplastic carcinoma of the breast: a multi-institutional study. Br J Cancer 112, 283-9 (2015).
3. Kobielak, A. & Fuchs, E. Links between alpha-catenin, NF-kappaB, and squamous cell carcinoma in skin. Proceedings of the National Academy of Sciences of the United States of America 103, 2322-7 (2006).
4. Finegan, K.G. et al. ERK5 is a critical mediator of inflammation-driven cancer. Cancer Res 75, 742-53 (2015).
5. De Robertis, M. et al. The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies. Journal of carcinogenesis 10, 9 (2011).

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