Investigating the effect of high fat diet on early pancreatic cancer

D'Ambrogio, Joshua 2025. Investigating the effect of high fat diet on early pancreatic cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Cell competition is a homeostatic tissue protective mechanism that compares the relative fitness between neighbouring cells leading to the creation of ‘winner’ and ‘loser’ cells. Pancreatic cancer has a 5-year survival rate of 7%, with pancreatic ductal adenocarcinoma (PDAC) being the most prevalent pancreatic neoplasm, often initiated by a KrasG12D mutation. At the initial stages of tumorigenesis, transformation occurs in a single cell within a healthy epithelial sheet. We recently showed that cell competition occurs in adult pancreas when KrasG12D mutations are expressed in low numbers of cells in an otherwise healthy tissue, demonstrating that competition triggers the elimination of KrasG12D cells from tissues. Obesity has been characterised as the most major modifiable risk factor in PDAC. However, the effect of obesity on the competitive elimination of KrasG12D mutant cells is poorly understood. Here I use low level, stochastic induction of KrasG12D mutant cells paired with high fat diet feeding to investigate how high fat diet effects elimination of mutant cells in the pancreatic epithelia. I show that high fat diet feeding inhibits the elimination of KrasG12D mutant cells only in the ductal compartment of the pancreas. In the acinar compartment and Islet of Langerhans I found regardless of whether high fat diet feeding was applied, KrasG12D mutant cells were not eliminated. I have shown that regardless of diet, tissue maturity attenuates the competitive removal of KrasG12D mutant cells we have observed previously. We have also illustrated the role of diet in this competitive dynamic, where high fat diet feeding decreased the competitive removal of KrasG12D mutant cells in the ductal compartment, as well as exacerbating the re-emergence of these mutant cells post clearance.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	3 February 2026
Last Modified:	10 Feb 2026 16:32
URI:	https://orca.cardiff.ac.uk/id/eprint/184373

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