Leveraging Macrophage Metabolism in Pancreatic Cancer
Primary Supervisor: Keaton Jones
Second Supervisor: Professor Eric O'Neill, Dr Anita Fallah
Project Overview
Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with fewer than 5% of patients surviving more than five-years. Unlike other solid tumours, PDAC has shown minimal response to immunotherapy, largely due to the profoundly immunosuppressive tumour microenvironment (TME). Tumour-associated macrophages (TAMs) dominate the TME and act as critical regulators of antitumour immunity. Recent studies indicate that the metabolic state of TAMs is central to their functional programming, yet the pathways underpinning immunosuppressive versus immune-stimulatory states remain poorly defined. Aims and Approach This DPhil project will employ complementary experimental and computational strategies to investigate the metabolic vulnerabilities of TAMs in PDAC. The first phase (years 1 – 2) will involve comparative murine models of immunotherapy sensitivity. We have both immunotherapy sensitive (Y) and resistant (F) PDAC models that will provide insights into TAM biology in the context of responding and non-responding tumours.
1. Metabolomic Profiling of Tumour Macrophages TAMs in immunotherapy sensitive (Y) and resistant (F) murine PDAC tumours will be analysed by mass cytometry by time of flight (CyTOF) and imaging mass cytometry (IMC) to define their metabolic profile and spatial organisation within the TMA.
2. Metabolite identification In vitro educated macrophages and tumour isolated macrophages will be analysed by LC-MS mass spectrometry to identify differences in metabolites including those involved in specific pathways and also secreted.
3. Translation to Human Disease Primary human pancreatic cancer specimens will be collected and analysed by RNA sequencing, IMC and CyTOF to resolve similarities with murine data, aiding clinical translation.
Impact This project will define how macrophage metabolism shapes the PDAC immune microenvironment, providing mechanistic insights and identifying therapeutic strategies to reprogramme macrophages and enhance immunotherapy response. It is further strengthened by the opportunity to validate findings using human PDAC specimens.
Training Opportunities
The student will gain training in:
- Primary macrophage culture and polarisation
- Preparation and analysis of samples for LC-MS metabolomics
- Bioinformatic and statistical analysis of metabolomic datasets
- Imaging mass cytometry: image processing, segmentation, and single-cell spatial analysis
- Visualisation and interpretation of multi-omic data
- Comparative analysis of murine and human PDAC samples
- Presentation of findings for lab meetings, conferences, and publications
This structured training will equip the student with a strong interdisciplinary skill set spanning cancer immunology, metabolism, and computational biology, preparing them for a career in translational oncology research.
References
O’Neill, L.A. and Pearce, E.J., 2016. Immunometabolism governs dendritic cell and macrophage function. Journal of Experimental Medicine, 213(1), pp.15-23.
https://rupress.org/jem/article/213/1/15/41869/Immunometabolism-governs-dendritic-cell-and