The neoplastic potential of pancreatic cell populations

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic
cancer, is the third leading cause of cancer-related deaths. Because of late diagnosis and a lack of effective therapies, it is necessary to understand the molecular pathology in the context of predisposing conditions. Pancreatitis is a typical example of a predisposing condition that induces dedifferentiation of pancreatic acinar cells, with activation of embryonic markers reminiscent of duct cells, making them susceptible to tumour development. This PhD project aimed at understanding this first step in pancreatic tumorigenesis by studying dedifferentiated acinar cells both in human and mouse adult pancreas and during embryonic development of the mouse pancreas. Specifically, the first objective was to uncover the difference in transcriptional expression profile between dedifferentiated (duct cell-like) acinar and native duct cells and to identify a transcription factor, MECOM, uniquely expressed in dedifferentiated acinar cells that had priority for further investigation in the context of tumor development; the second objective was to characterize this specific transcription factor in the context of acinar
dedifferentiation and pancreatic tumor formation and the third objective to study
the priority transcription factor in pancreatic embryonic development. Loss of MECOM resulted in a distinct phenotype with impaired cell adhesion, more prominent cell death and suppressed acinar cell dedifferentiation by limiting ERK signaling, but its role seemed redundant during embryonic development of the pancreas. Together, this gives us more insight in the early steps that facilitate tumor formation.