Dissecting the Roles of Cancer-Associated Fibroblasts and Key Underlying Signalling Pathways in Regulating Stemness in Pancreatic Cancer
Supervisors: Dr Peter Wan, Dr Kerry Fisher
Project Overview
This project will focus on the regulation of cancer stemness in pancreatic ductal adenocarcinoma (PDAC), investigating how cancer-associated fibroblasts (CAFs) contribute to the maintenance of stem-like tumour cell populations. Cancer stemness underpins tumour initiation, plasticity, progression, and resistance to therapy, yet the mechanisms by which the CAFs reinforce these properties remain poorly understood. CAFs are a heterogeneous population, including inflammatory CAFs (iCAFs), myofibroblastic CAFs (myCAFs), antigen-presenting CAFs (apCAFs), and many others, each with distinct phenotypes and functions. The project will investigate which CAF subsets most strongly support PDAC stemness and the molecular pathways through which this occurs. While several pathways such as Wnt/β-catenin, Notch, and Hedgehog are well known to regulate stemness, the specific role of CAFs in modulating these pathways remains unclear. Moreover, different CAF subtypes may contribute to stemness through distinct mechanisms, and it is possible that additional, as yet unidentified, signalling cascades are also involved. This project will therefore aim not only to evaluate established pathways but also to uncover novel CAF–tumour interactions that sustain stemness in PDAC. The experimental work will begin with the isolation of CAFs from patient-derived material, including ascites and resected pancreatic tumour biopsies, alongside induction of CAFs from normal fibroblasts and pancreatic stellate cells. These fibroblast populations will then be co-cultured with pancreatic cancer cells. Stemness will be assessed using functional assays, including sphere formation and serial propagation assay to directly measure the influence of CAFs on cancer cell stem-like behaviour. In addition, the project will investigate the signalling between CAFs and tumour cells that drive stemness, using pathway inhibition approaches to dissect the contribution of specific axes. There will also be scope to employ bioinformatic analyses to complement the wet-lab work, for example by exploring the spatial organisation of CAF subtypes and stemness niches within tumour tissue. Together, these approaches will provide a comprehensive understanding of how CAF heterogeneity sustains cancer stemness in PDAC and identify critical stromal–tumour pathways that could be targeted to suppress stemness and improve therapeutic response.
References
Murthy, D., Attri, K.S., Shukla, S.K., Thakur, R., Chaika, N.V., He, C., Wang, D., Jha, K., Dasgupta, A., King, R.J. and Mulder, S.E., 2024. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2–SP1–SAT1 axis. Nature cell biology, 26(4), pp.613-627.