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Studentship: Recapitulating the post-surgical brain microenvironment of atypical teratoid/rhabdoid tumours to identify proteins for targeted therapy’

Reference
MED1614
Closing Date
Sunday, 31st July 2022
Department
Centre for Biomolecular Sciences

Biodiscovery Institute, Children’s Brain Tumour Research Centre, School of Medicine & School of Life Sciences – (Brain Cancer / Proteomics)

PROJECT:

Childhood atypical teratoid/rhabdoid tumours (AT/RT) are aggressive neoplasms predominantly occurring in the hindbrain, for which prognoses remains a dismal median survival of 17 months. The high frequency of AT/RT patients <3 years old complicates radiation therapy due to debilitating neurological effects, and surgery remains the only standard therapy. Not only are efficacious and safe chemotherapeutics warranted, but scientific adherence to the precise clinical need (i.e., greater understanding of AT/RT residual disease post-surgery), and pathophysiological models which mimic this clinical snapshot, are urgently required for rational repurposing of molecular targeted drugs. 

This 3-year PhD project funded by the Grace Kelly Childhood Cancer Trust, aims to model the interaction of AT/RT cells with healthy brain cells from the cerebellum, to better understand how signals from the tumour microenvironment promotes the survival and propagation of recurrent AT/RT post-surgery. A panel of fluorescently tagged patient-derived AT/RT cells will be co-cultured with cerebellar astrocytes and decellularised human brain extracellular matrix (ECM). This will ensure that this 3D model (which we term ‘Tumoursphere Matrix’) is physiologically accurate, where AT/RT cells receive signals from healthy astrocytes and brain-specific ligands from the ECM. 

Upon co-culture, fluorescence-activated cell sorting will be used to separate AT/RT and astrocyte cell populations, and mass spectrometry-based proteomics on plasma membrane fractions conducted. Computational analyses of each co-cultured cell type (and relative to monolayer cultures) will reveal unique/differentially expressed membrane proteins induced on AT/RT cells. The outcome – a cell-surface protein map amenable for drug repurposing, to abrogate AT/RT survival mechanisms in the post-surgical brain milieu. 

The Tumoursphere Matrix model will finally be used as a screen to assess a library of drug compounds to identify repurposed therapeutics which impair AT/RT growth and invasion.

ENVIRONMENT:

The Children’s Brain Tumour Research Centre (CBTRC) brings together multidisciplinary researchers from clinical, translational, and basic science arenas focused upon testing hypotheses generated by the clinical needs of the child or young person, presenting with a tumour of the central nervous system. The Centre links researchers from ten departments across the University and Nottingham University Hospital Departments conducting clinical and scientific research directed at increasing our understanding of the biological nature of childhood brain tumours and using this knowledge to optimize the health outcomes for the child and family.

CBTRC is housed within the University of Nottingham’s flagship Biodiscovery Institute (BDI). The recently completed £23M expansion that opened in Dec 2019 extends BDI to a £100M interdisciplinary complex of four interconnected buildings at the heart of main campus to house nearly 1000 academic, clinical and support staff, as well as very strong postgraduate student representation. The School of Life Sciences, the largest Life Sciences department in the UK, is co-located and provides expertise and state-of-the-art facilities for protein profiling and analyses.

The PhD project will be supervised by Dr. Ruman Rahman (Associate Professor of Molecular Neuro-Oncology) and Prof. Robert Layfield (Professor of Protein Biochemistry). 

TO APPLY:

Applicants should hold, or expect to hold, a first or upper second-class degree in one of the following disciplines: Molecular/Cellular Biology, Genetics or Biochemistry. Completion/near completion of an MSc or MRes course is desirable. 

This studentship is available from October 2022 for a period of 3 years. Fees will be covered with a starting stipend of £16,352 with an annual incremental increase. The studentship is only available to students from the UK and Ireland due to funding restrictions.

To apply, prospective applicants should send a 2-page CV and cover letter to  ruman.rahman@nottingham.ac.uk and copying in robert.layfield@nottingham.ac.uk