As part of the successful CRUK accelerator award studying the microenvironment in hepatocellular carcinoma (HCC), we are looking for a graduate student to be jointly supervised by Dr Matthew Hoare at the Cancer Research UK Cambridge Institute and Dr Meritxell Huch at the Gurdon Institute.
Cellular senescence is a highly conserved tumour suppressor mechanism, whereby cells undergo permanent cell cycle arrest in response to diverse stressors such as replicative exhaustion, oxidative stress and unrestricted oncogene-activation (1). Senescent cells accumulate in the diseased human liver (2), are enriched in areas of dysplasia (3) and their presence predicts the subsequent development of HCC (4). Mouse models of hepatocyte replicative senescence develop features of liver failure (5).
Despite being non-proliferative senescent cells are both metabolically active and highly secretory, driving non-autonomous effects that can be both tumour suppressive and pro-oncogenic dependent on context (6). Through signalling to immune cells they trigger their own immune-mediated clearance, termed senescence surveillance (7). When this process is interrupted senescent cells persist and are chronically oncogenic. The mechanism for this pro-oncogenic effect, though, remains elusive.
We have demonstrated that RAS-senescent hepatocytes drive signalling in adjacent hepatocytes (8), but the functional effect of non-autonomous signalling from persistent senescent cells to surrounding ‘normal’ hepatocytes is unknown. Also, whether persistent intrahepatic senescent cells drive pro-oncogenic signals or inhibit the normal function of adjacent cells is unknown. Novel organoid culture systems that allow long-term expansion of liver progenitors that retain the capacity to differentiate in to hepatocytes in vitro represent an ideal model to study the interactions of two or more cell populations in a more physiological context (9).
We hypothesize that senescent hepatocytes have significant non-autonomous effects upon:
1) the transcriptional programme and chromatin architecture of adjacent normal hepatocytes;
2) the functionality of adjacent normal hepatocytes.
Aims and experimental design
We aim to utilise liver organoid-based models to study non-autonomous signalling from senescent hepatocytes to adjacent normal cells and utilise these models to understand the functional effects of senescence in the pre-cancerous liver microenvironment.
Please refer to the additional information for this Studentship.
The ideal candidate will have a solid knowledge of cell or cancer biology and experience in one or more of the areas mentioned above. He or she must be highly motivated to drive an independent research project.
This project is funded by a Cancer Research UK studentship that includes full funding for University and College fees and a stipend of £19,000 per annum.
The studentship provides a maintenance grant and tuition fees at the UK/EU rate. Owing to funding restrictions the studentship is not available to non-EU nationals.
Applications are invited from recent graduates or final year undergraduates who hold or expect to gain a first/upper second class degree (or equivalent) in a relevant subject from any recognised university worldwide.
How to apply
All applications need to be made using the University Applicant Portal. Please visit: https://www.graduate.study.cam.ac.uk/courses/directory/cvcrpdmsc for further information about the course and to access the applicant portal.
To complete your on-line application, you need to provide the following:
Reference Request: The names and contact details of two academic referees who have agreed to act on your behalf.
Research: If you wish to be considered for more than one studentship, please enter the names of all of the supervisors you wish to consider your application in the ‘Research summary’ text box. If you only wish your application to be considered by a single supervisor, then please enter their name in the ‘Research Supervisor’ text box. Please describe your past ‘Research experience’ in the appropriate text box.
Course Specific Questions: Your statement of interest (limit of 2,500 characters) should explain why you wish to be considered for the studentship and which qualities and experience you will bring to the role. Please also state how you learned of the studentship.
Supporting Documents: Please upload your CV (PDF file), which should include a list of the examinations taken at undergraduate level and if possible, your examination results
The closing date for applications is 30 November 2018, with interviews expected to take place in December/January.
Please quote reference SW17250 on your application and in any correspondence about this vacancy.
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