We are using mouse models and patient samples to understand the origins of pancreatic cancer and the mechanisms driving its development.
Pancreatic adenocarcinoma (PDAC) has the lowest survival rate of all cancer types and is typically diagnosed late, making it difficult to investigate disease progression. The cell of origin of PDAC is still a topic of debate. Acinar cells can adopt a duct-like fate and subsequently give rise to PDAC through a process called acinar-to-ductal metaplasia, and we showed that this is mediated by the Hippo and JAK/STAT pathways (Gruber et al., 2016).
Moreover, we recently showed that PDAC can arise not only from acinar cells, but also from ductal cells, and identified AGR2 as a specific marker that discriminates duct- and acinar-derived PDAC in mice. AGR2 expression also stratified human PDAC samples (Ferreira et al., 2017). Duct- and acinar-derived PDAC showed distinct biological features and effects on survival (Ferreira et al., 2017).
We want to understand the molecular mechanisms driving PDAC development from these different cells of origin, and we are using advanced mouse genetics to analyse the biology of these PDAC subtypes. Moreover, we have access to freshly resected human PDAC material from King's College Hospital, one of the largest centres for PDAC surgery in the UK. Growing these donated patient samples as PDAC cancer organoids, we are characterising human PDAC subtypes stratified by their gene and protein expression, to identify features that could determine prognosis or treatment.