Identifying Metabolic Vulnerabilities in Classical and Basal-like PDAC Through Patient-Derived Organoids
Supervisors: Dr Peter Wan, Dr Kerry Fisher
Project Overview
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a five-year survival rate of less than 10%. Despite advances in characterising its molecular landscape, effective therapeutic options remain limited. Transcriptomic studies have identified two main PDAC subtypes: classical, associated with epithelial differentiation markers such as GATA6 and a relatively better prognosis, and basal-like, which is more aggressive and strongly linked to therapy resistance and poor outcome. Emerging evidence indicates that these subtypes are supported by distinct metabolic states. Classical tumours tend to display greater glycolytic activity, whereas basal-like tumours rely more on mitochondrial oxidative metabolism. These metabolic programmes may underpin the different biological behaviours and therapy responses of the subtypes. However, their consistency across patient-derived samples and their relevance as therapeutic targets remain poorly understood. This project will use patient-derived organoids (PDOs) to systematically investigate the metabolic requirements of classical and basal-like PDAC. Organoids stratified by subtype will be cultured under defined nutrient and stress conditions, such as glucose or glutamine restriction and hypoxia, to assess how metabolism influences survival and growth. Functional assays will include organoid-forming ability, serial propagation, and extracellular flux analysis to quantify glycolytic and oxidative capacity. Key metabolic pathways will be directly targeted using specific inhibitors or nutrient interventions, to test whether subtype-specific vulnerabilities can be exploited and whether intervention in metabolism may shift tumours between basal-like and classical states. This is a highly translational project. By handling primary pancreatic cancer biopsies to establish PDOs, you will work closely with clinical and translational research teams. This will provide both access to clinically relevant material and the opportunity to ensure that discoveries in organoid systems are aligned with patient biology and therapeutic development.
References
Daemen, A., Peterson, D., Sahu, N., McCord, R., Du, X., Liu, B., Kowanetz, K., Hong, R., Moffat, J., Gao, M. and Boudreau, A., 2015. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proceedings of the National Academy of Sciences, 112(32), pp.E4410-E4417.