Pancreatic cancer is one of the world's deadliest cancers, with a 5-year survival rate of only ~10%.
The majority of patients present with late-stage disease and effective therapeutic options are
limited. Ultimately, ~90% of patients diagnosed with pancreatic cancer will eventually die of their
disease. Only minor improvements have been made over the last decade, and concerningly, the
incidence of pancreatic cancer continues to rise each year. In order to improve patient outcomes,
a better understanding of the genetic drivers of pancreatic cancer is necessary.
One such driver is loss of functional TP53, a tumour suppressor gene which is mutated in ~70%
of pancreatic cancer cases. TP53 is a transcription factor directly regulating around 500 target
genes, many with roles in critical cellular processes such as apoptosis, cell cycle arrest, cellular
senescence, DNA repair and coordination of metabolism. Mutant TP53 proteins can contribute to
tumour development in several ways, including loss of WT TP53 function, dominant negative
effects, and gain-of-function activities.
In this project, we will generate genetically modified pancreatic organoids that have been
engineered to allow controlled switching of TP53 from a WT state to a mutant state, and at a later
time point, back to a WT or into a TP53 KO state. We will utilise this model to characterise cellular
changes that occur upon TP53 state switching. These investigations will provide insight into the
mechanisms by which mutant TP53 contributes to the development and sustained survival of
pancreatic cancer, with the aim of identifying new therapeutic strategies to improve patient
outcomes.