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Understanding the role of Epstein Barr virus in gastric carcinoma


Project Description

BACKGROUND
Epstein Barr virus is a common herpesvirus that is strongly associated with the pathogenesis of at least seven different cancers. Of these cancers, gastric carcinoma (GC) is the most frequently observed throughout the world. However we have very little understanding of how EBV drives the pathogenesis of GC. It is becoming increasingly evident that viruses do not trigger the genetic mutations associated with cancer; instead they initiate genome-wide epigenetic changes that drive the carcinogenesis. This is clearly evident in GC where few genetic mutations are consistently detected but an excessively hypermethylated cellular genome is always apparent. The project will integrate ex-vivo and in-vitro studies of EBV-infection of gastric epithelial cells and will investigate the role of both EBV and the immune microenvironment in driving the formation of GC.

AIMS
The proposed project will focus on three key aspects of gastric carcinogenesis. Firstly, the successful applicant will examine the genetic differences between each stage of gastric disease and correlate the cellular gene expression profiles with disease status. Secondly, the applicant will examine the immune infiltrate and inflammatory profile of each stage of gastric disease and again correlate this with the cellular gene expression profile. Finally, the applicant will establish organoids from each disease stage and infect the organoids with EBV to determine when during disease progression the virus exerts its oncogenic potential and generates cellular changes consistent with disease progression and cellular transformation.

METHODS
1. Using RNAseq, we will identify gross changes in the cellular gene expression profile and correlate these changes with disease status. The changes will be validated by immunohistochemistry directly on the biopsy samples.
2. Infiltrating lymphocytes will be isolated and phenotyped by multicolour flow cytometry or CyTOF. We will employ in-house immunophenotyping panels to examine the phenotype and function of the infiltrating lymphocytes and determine how this population changes with disease state.
3. We will establish organoids from each disease stage and infect the gastric epithelial cells with EBV. We will monitored the infected organoids over time by global methylome analysis to identify cellular epigenetic changes that correlate with disease status and immune infiltrate. We have well established organoid technology and a wealth of expertise in virological, immunological, sequencing and bioinformatics technologies.

This work will provide an in depth training in many cellular, molecular and immunological techniques including flow cytometry and CyTOF, Q-PCR, RNAseq, global methylome analysis, confocal microscopy and organoids. The development of organoids has been one of the break-through technologies that has helped advance our understanding of many different cancers and will be critical to the success of this project.

Person Specification
Applicants should have a strong background in Biomedical Science, and ideally a background in Cellular/Molecular Biology. They should have a commitment to research in cancer biology and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Biomedical Sciences.

How to apply
Informal enquiries should be directed to Dr Claire Shannon-Lowe
Applications should be directed to Dr Claire Shannon-Lowe (email ).
To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

Applications are invited from Self-Funding applicants only.
Students will be expected to bring a consumables budget of £20,000 per year.

References

1. Comprehensive molecular characterization of gastric adenocarcinoma. Cancer Genome Atlas Research Network. Nature. 2014 Sep 11;513(7517):202-9

2. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Bartfeld S, Bayram T, van de Wetering M, Huch M, Begthel H, Kujala P, Vries R, Peters PJ, Clevers H. Gastroenterology. 2015 Jan;148(1):126-136.e6

3. Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Chiba T, Marusawa H, Ushijima T. Gastroenterology. 2012 Sep;143(3):550-563.

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