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  (MRC DTP CASE) Understanding how tumour associated macrophages control the tumour immune landscape in NF2-Schwannomatosis


   Faculty of Biology, Medicine and Health

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  Prof David Brough, Dr Kevin Couper  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Type 2 Neurofibromatosis (NF2), now referred to as NF2-Schwannomatosis (or NF2-SWN), is a rare autosomal dominant tumour pre-disposition syndrome characterised by growth of typically benign tumours throughout the nervous system. The development of bilateral vestibular schwannoma (VS) tumours – brain tumours arising on the vestibular nerves – is pathognomonic for NF2-SWN. Individuals with NF2-SWN experience multiple tumours throughout their lifetime that cause significant morbidity including profound deafness, and which can lead to brain stem compression, hydrocephalous and early death. Surgery and/or radiotherapy are the currently available treatments for NF2-SWN VS. However, all have significant drawbacks and new therapeutic strategies are urgently needed.

We know from our own and others’ published data that the tumour immune cell compartment significantly influences the growth of, and symptoms associated with, NF2-SWN VS. However, we do not yet understand how the immune compartment is regulated within the tumour, how immune cells enter and localise within the tumour, and precisely how immune cell populations function to determine tumour growth and clinical trajectory. In particular, although tumour associated macrophages (TAM) infiltration appears to correspond with VS tumour growth, and TAMs appear to restrict T cell surveillance and killing within the tumour, how they mediate these pathogenic effects is poorly understood.

The aim of this PhD is to resolve how macrophage-dependent inflammation contributes to VS growth and clinical trajectory using a combination of cell culture systems containing NF2 knock out macrophages and tumour cells, preclinical models and intervention studies, with validation in human brain tumour samples. The project will directly investigate the tumour signals that control the recruitment and polarisation of TAMs in the tumour, the pathways that control the positioning and colocalisation of TAMs with tumour cells, and how the TAMs regulate T cell functionality. The work proposed here will lead to the identification of new intervention strategies for individuals with NF2-SWN.

The successful candidate will gain an excellent training in cancer immunology and will receive training in various cutting edge immunological techniques including imaging mass cytometry, spectral flow cytometry and confocal and immunofluorescence microscopy, all combined with in vivo training with a number of novel transgenic murine strains. Thus, the successful candidate will obtain essential interdisciplinary and quantitative in vivo skills to support their future career. 

Eligibility

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC DTP website https://www.bmh.manchester.ac.uk/study/research/funding-fees/funded-programmes/mrc-dtp/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Biological Sciences (4) Medicine (26)

Funding Notes

This is a 4 year CASE studentship in partnership with NF2 BioSolutions UK & Europe. This scheme is open to UK applicants only. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

Gregory GE, Jones AP, Haley MJ, Hoyle C, Zeef LAH, Lin IH, Coope DJ, King AT, Evans DG, Paszek P, Couper KN, Brough D, Pathmanaban ON.
The comparable tumour microenvironment in sporadic and NF2-related schwannomatosis vestibular schwannoma.
Brain Commun. 2023 Jul 21;5(4):fcad197.
Green JP, El-Sharkawy LY, Roth S, Zhu J, Cao J, Leach AG, Liesz A, Freeman S, Brough D.
Discovery of an AIM2 inflammasome inhibitor for the treatment of DNA-driven inflammatory disease
iScience. 2023, 26:106758.
Lee B, Hoyle C, Wellens R, Green JP, Martin-Sanchez F, Williams DM, Matchett BJ, Seoane PI, Bennett H, Adamson A, Lopez-Castejon G, Lowe M, Brough D.
Disruptions in endocytic traffic contribute to the activation of the NLRP3 inflammasome
Science Signaling. 2023, 16(773):eabm7134.
Hannan CJ, Lewis D, O'Leary C, Waqar M, Brough D, Couper KN, Dyer D, Vail A, Heal C, Macarthur J, Cooper C, Hammerbeck-Ward C, Evans DG, Rutherford SA, Lloyd SK, Freeman SRM, Coope DJ, Roncaroli F, King AT, Pathmanaban ON,
Macrophage infiltration is associated with faster growth and increased vascularity in a large cohort of sporadic vestibular schwannomas
Neurosurgery. 2022, 92(3):581-589.
Rivers-Auty J, Tapia VS, White CS, Daniels MJD, Drinkall S, Kennedy PT, Spence HG, Yu S, Green JP, Hoyle C, Cook J, Bradley A, Mather AE, Peters R, Tzeng TC, Gordon MJ, Beattie JH, Brough D, Lawrence CB.
Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation.
J Neurosci. 2021, 41:3025-3038.