Lipidome atlas of p53 mutant variants in pancreatic cancer

Mutations in the tumour suppressor protein p53 are present in 70% of human pancreatic ductal adenocarcinomas (PDAC), subsequently to highly common activation mutation of the oncogene KRAS. These p53 mutations generate stable expression of mutant proteins, such as p53^R175H and p53^R273H, which do not retain p53 wild type function. In this study, we investigated the impact of two specific p53 mutant variants on lipid metabolism of pancreatic cancer. Lipids critically participate to tumorigenesis with to their roles in membrane biosynthesis, energy storage and production of signalling molecules. Using cell lines derived from mouse models of PDAC generated by knock-in p53 alleles carrying point mutations at codons R172H and R270H (equivalent to R175H and R273H in humans), we found that silencing p53^R172H and p53^R270H in pancreatic cancer cells significantly alters lipid metabolism, with patterns of common and variant specific changes. Specifically, loss of p53^R172H in these cells reduces lipid storage. Additionally, silencing either p53^R172H or p53^R270H individually leads to marked increases in lysophospholipid levels. These findings offer new insights into the lipidome reprogramming induced by the loss of mutant p53 and underscore changes in lipid storage as a potential key molecular mechanism in PDAC pathogenesis.