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Defining the role of a novel colorectal cancer tumour suppressor gene (TSG) at the frequently deleted 1p22 locus.

   Barts Cancer Institute

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  Dr A Cameron, Prof Trevor Graham, Dr S McDonald  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

London United Kingdom Biochemistry Bioinformatics Cancer Biology Cell Biology Evolution Genetics Molecular Biology

About the Project

Project Details: Inflammatory Bowel Disease is associated with a significant increase in risk for the development of colorectal cancer (CRC). Using an in vivo model of inflammation associated colon cancer we have identified a novel tumour suppressor gene (TSG). Genetic disruption of this novel TSG dramatically sensitises mice to colon tumour development. Critically, the gene is encoded at the 1p22 locus which is deleted in almost a third of CRC cases but the reason for this recurrent loss remains to be explained. Understanding how loss of this TSG contributes to inflammation induced tumorigenesis can thus improve our understanding of how colorectal tumours evolve.

In this project we will first assess the mechanism underlying enhanced tumour formation in our laboratory model. We will use a combination of transcriptomics and pathology to examine which pathways are modulated in normal tissue, dysplasia and colon tumours. Work in cell models will seek to identify molecular mechanisms regulated by the tumour suppressor in colon cancer cells, which can be validated in our in vivo model. Excitingly, evidence suggests this tumour suppressor may regulate tumour inflammation and immune cell content, which is a critical prognostic indicator and marker for predicting response to immunotherapy. Next, we will use CRC patient samples, in conjunction with bioinformatic approaches and AI driven digital pathology to explore the relationship between 1p22 loss tumour suppressor function in human CRC.

Although we have demonstrated that our new TSG has a role in an inflammatory model, 1p22 is also lost in sporadic-CRC and other tumour settings including melanoma and multiple myeloma. This raises the possibility that defining this new tumour suppressor pathway may have broad impact in cancer research. CRC alone is the second biggest cause of cancer death; approximately 17,000 patients die each year in the UK and the majority of these are diagnosed at an advanced stage where 5-year survival is approximately 10%. As loss of 1p22 may occur in around 30% of these cases, identifying a new tumour suppressor would mark a significant advance for the field. This work can directly impact a third of poor outcome colorectal cancer patients,

This project thus represents an exciting opportunity to define an entirely novel tumour suppressor with broad implications for cancer research. 

Training and Support: The studentship will take place at Barts Cancer Institute under the supervision of Dr Cameron and Professor Graham. Dr Cameron is an expert in novel cancer drug targets, currently focussing on pancreatic and colorectal cancer. His laboratory focuses on in vivo tumour models, cell biology and drug discovery. Professor Graham is a leading expert in cancer evolution and applies a broad range of mathematical and bioinformatic approaches to understand how colorectal tumours develop and evolve into malignant disease. The project is also supported by Dr Stuart McDonald (BCI) a leading expert in gastrointestinal tumorigenesis, tumour evolution and intestinal pathology.

Barts Cancer Institute is a world-class cancer research institute in the UK, performing basic and clinical research. In 2018 the BCI joined the Francis Crick Institute, King’s and UCL to form the CRUK City of London Major Centre. Advanced Microscopy Imaging, pathology, tissue banks and bioinformatics complete a robust infrastructure to deliver this project.

This project is an ideal opportunity for a clinical fellow working in oncology, gastroenterology or pathology, with ambitions to work as a clinician scientist. The project will provide the opportunity to work primary human tissue and has huge translational potential. Professor Graham has a proven track record working with clinical fellows and Dr Cameron currently has two clinicians in his research group. On completion of their PhD the successful candidate would be ideally placed to develop their own independent research plans and will have benefited from working in an institute with a proud history of translating basic science into clinical benefit.

Funding Notes:

The Trustees of The Medical College of Saint Bartholomew’s Hospital Trust (MCSBHT) have offered funding for a research studentship from the Willoughby Fund, for a clinically qualified candidate to commence in October 2022, leading to a PhD degree from The QMUL Faculty of Medicine and Dentistry.

This studentship will fund a student with a clinical qualification and GMC / GDC registration at any career stage below consultant. The Studentship will cover the successful candidate’s current clinical salary and will include PhD fees (at home fee rate) with up to £6000 pa for consumables. Further consumables / funding for travel may be available on application. 

Notice on Equality, Diversity and Inclusion: Barts and The London School of Medicine and Dentistry aims to promote an organisational culture that is respectful and inclusive irrespective of age, disability, gender reassignment, ethnicity, marriage or civil partnership, pregnancy and maternity, race, sex and religion or belief. Moreover, it seeks to ensure that intersectionality is recognised, with explicit acknowledgement of the interconnected nature of social identities including race, class and sex, where these facets can create overlapping levels of discrimination or disadvantage.

Application Web Page: https://mysis.qmul.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RFQM-W3ZF-09&code2=0013

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