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Pancreatic cancer is a lethal disease with a dismal prognosis, with an overall 5-year survival rate of less than 9%. Pancreatic Cancer UK has launched a Future Leaders Academy to improve our understanding of tumour-stromal and tumour-immune interactions in the hope of identifying therapeutic targets in pancreatic ductal adenocarcinoma (PDAC).

The most common type of pancreatic cancer (PDAC) is characterized by its striking fibroinflammatory stroma, which constitutes some 90% of tumour bulk. The stroma is generally thought to promote tumour growth by inhibiting the tumour immune system, providing growth factors and contributing to PDAC therapeutic refractoriness by impeding vascular perfusion and oxygenation, although recent evidence suggests that elements of the stroma have tumour-restraining properties.

Strategies targeting the stroma in PDAC have so far focused mainly on fibroblasts, specific components of the extracellular matrix such as hyaluronan, or angiogenesis. Although preclinical results were promising, in most cases this did not translate in the clinical setting. Pancreatic tumours are also resistant to immunotherapies that work in other cancers, such as PD-1/PD-L1 immune checkpoint blockade and anti-CTLA-4 antibodies. There is, therefore, a need for further research into the microenvironment of pancreatic tumours, to understand the interactions that influence pancreatic tumour development and growth, and to overcome resistance to treatment.

Dr Giulia Biffi wishes to appoint a student to work on the project entitled: Genetic and epigenetic basis of fibroblast heterogeneity, plasticity and functions in pancreatic cancer. For further information about the research group, including their most recent publications, please visit their website - https://www.cruk.cam.ac.uk/research-groups/biffi-group

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.

Further reading:

  1. Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, et al. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFbeta to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov 2019;9(2):282-301 doi 10.1158/2159-8290.CD-18-0710. PMC6368881.

  2. Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 2017;214(3):579-96 doi 10.1084/jem.20162024. PMC5339682.

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 (Giulia.Biffi@cruk.cam.ac.uk).

Funding:
This studentship is funded by the Pancreatic Cancer UK Future Leaders Academy that includes full funding for University and College fees, a stipend of £19,000 per annum over a period of 4 years, and funding for consumables.

Eligibility
No nationality restrictions apply to this studentship. Applications are invited from recent graduates or final year undergraduates who hold or expect to gain a first/upper second class degree (or equivalent) or Master's degree 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.

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.

The closing date for applications is 22 November 2020, with interviews expected to take place in December/January.

Key Information

Cancer Research UK Cambridge Institute

Reference: SW24414

Dates and deadlines:

Published
Wednesday, 14 October, 2020
Closing Date
Sunday, 22 November, 2020