Genetic and epigenetic basis of fibroblast heterogeneity, plasticity and functions in pancreatic cancer

Project details
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a five-year survival rate that remains below 10%. One of the key features of PDAC is the presence of dominant non-cancerous cellular and extracellular components, comprising the so-called stroma, which are partially responsible for the high mortality associated with PDAC. Among stromal cells, cancer-associated fibroblasts (CAFs) have been shown to promote tumour growth, chemotherapy resistance and immunosuppression. However, more recent evidence indicates that targeting of CAFs in PDAC may also have tumour-restraining functions. These seemingly conflicting studies underscore the need to better understand the complex nature and roles of CAFs, to identify effective therapeutic targets for PDAC.

Our Laboratory focuses on investigating CAF heterogeneity, plasticity and biology using in vitro three-dimensional, pancreatic tumour organoid/fibroblast co-cultures and in vivo orthotopic transplantation and genetically engineered mouse models of PDAC.

This project will focus on defining the genetic and epigenetic programmes that determine CAF heterogeneity, plasticity and functions. (1) We have identified a number of transcription factors (TFs) that are differentially expressed and/or active in different CAF subtypes and thus may represent master regulators of these cell states. We aim to further investigate the roles of these TFs by employing CRISPR/Cas9 technology in CAFs. (2) In addition, we aim to determine differences in the epigenome in distinct CAF subtypes. For this purpose, we will assess genome-wide chromatin accessibility of different CAF populations using various techniques, such as ATAC-sequencing. Completion of this work will help clarifying the genetic and epigenetic basis of CAF heterogeneity, plasticity and functions in PDAC, providing new knowledge for the development of effective combinatorial treatments that target tumour-promoting fibroblast populations.

Qualifications/skills
This project is ideal for bright and motivated candidates seeking experience in in vitro and in vivo models of pancreatic tumour/stroma interactions and interested in bioinformatics. A background in molecular and cellular biology, and tissue culture techniques is needed. Experience in bioinformatics and analysis of genomic datasets (e.g. DNA and RNA sequencing) is preferred. The project will provide training in various methodologies and model systems, including ChIP-sequencing, ATAC-sequencing, organoid and mouse work, and drug and CRISPR/Cas9 screens in both organoids and fibroblast lines.

Further enquiries can be directed to Dr Giulia Biffi ([Email Address Removed]).

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.

Please indicate that you wish to be considered for Cambridge Trust funding.

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 in CRUK CI, 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.