European Molecular Biology Laboratory (Heidelberg) Featured PhD Programmes
University of Edinburgh Featured PhD Programmes
King’s College London Featured PhD Programmes
Brunel University London Featured PhD Programmes
University of Sheffield Featured PhD Programmes

Integrative analysis of BAP1-dependencies to identify novel therapeutic targets for uveal melanoma: learning lessons from the lung


Project Description

We are seeking an enthusiastic, dedicated individual to join a highly motivated cancer biology research team at the University of Liverpool. The successful applicant will be supervised by Prof Judy Coulson (https://www.liverpool.ac.uk/translational-medicine/staff/judy-coulson/) and Prof Sarah Coupland (https://www.liverpool.ac.uk/translational-medicine/staff/sarah-coupland/), together with Dr Joe Sacco and Dr Helen Kalirai. They will benefit from expert PhD training by a multi-expertise team in a diverse range of cell biology and molecular pathology techniques for ocular oncology research.

Uveal melanoma (UM) is an often aggressive intraocular tumour with a high propensity for liver metastases (~50%) and poor prognosis. Metastatic UM is strongly associated with mutation of BAP1. Mutation results in inactivation of the BAP1 protein, a deubiquitylase and tumour suppressor that regulates multiple cellular pathways through fundamental roles in protein stabilisation and transcription. BAP1 is also frequently mutated in malignant pleural mesothelioma (MPM), a cancer of the lung lining, while germline BAP1-mutations underpin a cancer predisposition syndrome where family members develop multiple cancers, most commonly UM and MPM. It remains unclear exactly how BAP1 functions as a tumour suppressor, or why BAP1-mutation is common to UM and MPM, two tumours with otherwise low mutational burden. In fact, somatic BAP1-mutation is infrequent in common epithelial cancers and BAP1 is an essential/fitness gene, suggesting cancers must reprogram essential pathways to adapt to BAP1 loss. We hypothesise this reprogramming generates vulnerabilities that provide therapeutically targetable Achilles’ heels, and have already identified candidates in MPM. Certain changes that are intimately dependent on BAP1 will likely be shared by UM. In this project we take a function-driven approach to identify novel BAP1-dependent adaptation in UM, by exploiting our multi-omics datasets from isogenic BAP1-mutated MPM models, and comparing these with data from high-risk UM. For the most compelling common BAP1-dependencies, we will validate their clinical significance by assessing expression in UM cell lines and tissues with defined BAP1-status. Where these indicate specific therapeutic sensitivities, we will assess candidate drug efficacy in representative UM models.

The project will provide experience in a variety of techniques including: mass spectrometry, integrative bioinformatics analysis of transcriptome and proteome datasets, realtime-PCR and western blotting, cell culture and cell biology, immunohistochemistry, and methods to evaluate the effect of siRNA depletion or inhibitor treatment on the behaviour of human cancer cells both in vitro and in a non-mammalian model system.

The Institute of Translational Medicine (ITM) (https://www.liverpool.ac.uk/translational-medicine/) houses the world-class MRC Centre for Drug Safety Science and Centre for Preclinical Imaging. ITM develops and nurture young talent for careers in academia, and has strong links with the pharmaceutical industry, where more than 100 former graduates hold senior positions. We run a prestigious and long-standing Wellcome Trust 4-year PhD program, and have an excellent track record in training PhD students, who engage with a doctoral training program and vibrant seminar series. Prof Coulson is based in Cellular and Molecular Physiology, which has an established reputation for excellence, hosting internationally recognised researchers with active research programs providing new insights into the molecular and cellular processes that underpin pathological diseases. We collaborate closely with colleagues in Clinical and Molecular Cancer Medicine, particularly the Ocular Oncology Group lead by Prof Coupland (http://www.loorg.org/). We are active members of the North West Cancer Research Centre at the University of Liverpool (https://www.liverpool.ac.uk/nwcrc/) directed by Prof Coupland.
The studentship will commence on 1st October 2019.

Applicants will have a first class or upper second class honours degree (or equivalent) in the biological sciences and some laboratory research experience. You may have additional masters level research experience in cell biology, biochemistry or cancer research. You will be expected to work both in a team and independently, take ownership of your project, and develop expertise in new areas as required.
Formal applications to should include a cover letter outlining your reasons for applying, curriculum vitae, and the names and contact details for at least two academic referees (at least one of whom can comment on your laboratory research skills).
Note that interviews will likely be scheduled for April 9th 2019.

The University of Liverpool is fully committed to promoting gender equality and ITM holds an Athena SWAN Silver Award in recognition of on-going commitment to ensuring these principles are embedded in all its activities and strategic initiatives.

Informal enquiries: Prof Judy Coulson,
Formal applications: Mrs Michelle Nelson,

Funding Notes

Eligibility: UK/EU students only. All applicants must satisfy the appropriate University English language requirements (IELTS score of 6.5). This 3-year PhD studentship is fully funded by the charity Fight for Sight, leading to the award of a PhD from the University of Liverpool.

Funding covers tuition fees (UK/EU), and research support, plus a stipend (starting at £17,000 per annum, tax free).

References

Sacco JJ, Kenyani J, Butt Z, Carter R, Chew HY, Cheeseman L, Darling S, Denny M, Urbé S, Clague MJ, Coulson JM. (2015) Loss of the deubiquitylase BAP1 modifies class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors. Oncotarget 6(15):13757-71.

Farquhar N, Thornton S, Coupland SE, Coulson JM, Sacco JJ, Krishna Y, Heimann H, Taktak A, Cebulla C, Abdel-Rahman M, Kalirai H. (2017) Patterns of BAP1 protein expression provide insights into the prognostic significance and the biology of uveal melanoma. J Pathology: Clinical Research, 4 (1):26-38. DOI: 10.1002/cjp2.86. eCollection Jan 2018.

Bailey FP, Clarke K, Kalirai H, Kenyani J, Shahidipour H, Falciani F, Coulson JM, Sacco JJ, Coupland SE, Eyers PA. (2018) Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics. Pigment Cell and Melanoma Research, 31(2): 253-266. DOI:10.1111/pcmr.12650.

JJ Sacco, H Kalirai, J Kenyani J, Figueiredo CR, JM Coulson, SE Coupland. (2018) Recent breakthroughs in metastatic uveal melanoma - a cause for optimism? Future Oncology 14(14):1335-1338. DOI: 10.2217/fon-2018-0116

Email Now

Insert previous message below for editing? 
You haven’t included a message. Providing a specific message means universities will take your enquiry more seriously and helps them provide the information you need.
Why not add a message here
* required field
Send a copy to me for my own records.

Your enquiry has been emailed successfully





FindAPhD. Copyright 2005-2019
All rights reserved.