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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 Martin Miller wishes to appoint a student to work on the project entitled: Interrogating tumour-associated mechanisms of immune escape in pancreatic cancer (http://www.miller-lab.org/)

How do cancers create a pro-tumourigenic microenvironment?

Project details

Aims and objectives - Our understanding of how cancer cells cooperate to evade the anti-tumour immune response is limited. We have recently performed immunogenomics characterisation of tumours in a metastatic setting and have started to delineate the molecular programmes that associate with distinct tumour-immune microenvironments that can co-co-exist within the same individual (Jiménez-Sánchez et al Cell 2017, Jiménez-Sánchez et al Nat Genetics 2020). The pancreatic tumour microenvironment is distinctively immune privileged, but the cancer-derived mechanisms that drive immunosuppression in this cancer type remain largely unknown. We hypothesize that heterogeneous cancer clones cooperate and create an immunosuppressive microenvironment facilitating progression of pancreatic cancer. Using in vitro and in vivo tumour models, this PhD project aims to uncover mechanisms of tumour-immune escape in pancreatic cancer by modelling interactions between tumour cells and immune cells at a multi-scale level.

Experimental plan - Using a combination of novel cell-selective labelling methods, mass cytometry, proteomics, and genomics as well as mouse tumour modelling, we will explore how tumour clonal heterogeneity (tumour cell lines derived from the KPC pancreatic cancer mouse model) modulates tumour-infiltrating immune cells and create unique tumour microenvironments during tumour progression using both in vitro and in vivo models. In vivo, the interactions between tumour clones and immune cells will be resolved in a spatial context in the local tumour microenvironment using imaging mass cytometry or multiparameter immunohistofluorescence of individual cells in tumour tissue slides.

The interactions between the tumour and the immune system will be resolved at the systemic level using single cell mass cytometry analysis of circulating immune cells in the blood of tumour-bearing mice. Modelling of tumour-immune interactions ranging from the single cell, to the microenvironmental, to the systemic levels will reveal mechanisms of tumour-mediated immunosuppression, which will be further investigated in follow-up experiments. The outcome will be a quantitative framework to interpret the balance between inflammation and tolerance within the tumour microenvironment of pancreatic cancer.

Further reading:

M. B. Gill, S. Koplev, A. C. Machel & M. L. Miller. Resolving tumour clonal heterogeneity and spatial complexity using nuclear tandem epitope protein (nTEP) barcoding. bioRxiv (2018).

Jiménez-Sánchez A, et al. Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nat Genet. 2020;52(6):582-593. doi:10.1038/s41588-020-0630-5

Jiménez-Sánchez A, et al. Heterogeneous Tumour-Immune Microenvironments among Differentially Growing Metastases in an Ovarian Cancer Patient. Cell. 2017 Aug 24;170(5):927-938.e20. doi: 10.1016/j.cell.2017.07.025.

Gauthier NP, Soufi B, Walkowicz WE, Pedicord VA, Mavrakis KJ, Macek B, Gin DY, Sander C, Miller ML. Cell-selective labeling using amino acid precursors for proteomic studies of multicellular environments. Nat Methods. 2013 Aug;10(8):768-73. doi: 10.1038/nmeth.2529. Epub 2013 Jun 30.

Qualifications/skills:

This is a great opportunity to work in a dynamic laboratory (www.miller-lab.org) where you will develop proficiencies in various techniques including but not limited to: 1) single cell barcoding technologies (Gill et al BioRxiv 2018), 2) 3D tumour co-culture models and in vivo mouse modelling, 3) genomics and proteomics (e.g. CTAP technology, Gauthier et al Nat Methods 2013), 4) analysis of clinical tissue samples and 5) experience in advanced bioinformatics, offering an exciting hands-on perspective of translational medicine. The successful candidate will already have experience in experimental biology or clinical research, have a strong drive for interdisciplinary research bridging both basic and translational sciences, and have the ambition to pursue an independent career as a research/clinician scientist.

This PhD studentship with be co-supervised by Dr. Michael Gill. Further enquiries can be directed to Dr Martin Miller (martin.miller@cruk.cam.ac.uk) or Dr. Michael Gill (michael.gill@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: SW24378

Dates and deadlines:

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