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Acinar cell plasticity in the adult mouse pancreas

Final Report Summary - ACINPLAST (Acinar cell plasticity in the adult mouse pancreas)

Metaplasia in the pancreatic acinar cell compartment is implicated in pancreatitis and is often a precursor for neoplasia and tumour lesionsin pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer deaths. We dispose of an in vitro model of acino-ductal metaplasia, starting from purified mouse pancreatic acinar cells. We use this model for gathering insights into the molecular mechanisms that govern this process.

During this Marie Curie ERG, we studied which signalling pathways are activated during isolation and cell culture, and contribute to the acinar cell dedifferentiation. This dedifferentiation constitutes the first phase in the metaplasia. Our results point at a very early (at the time of collagenase digestion of the tissue) activation of Ras signalling, and of its down stream MAPK and PI3K pathways . These results underscore the significance and the representativeness of the in vitro model, because the same Ras signalling pathway is recently defined to be crucial in the in vivo development of acinar-derived pancreatic ductal adenocarcinoma's.

We further show that in the metaplastic process, the cells lose their normal characteristics and seem to revert to a stage of dedifferentiation. They take on characteristics that are reminiscent of precursor cells and start to express stem cell markers. In the same line, we demonstrated that in the adult acinar cells undergoing culture-induced dedifferentiation, a molecular complex is formed that resembles the embryonic transcription factor complex and that explains the altered gene expression. Our results give insight into acinar cell plasticity and can eventually be used to prevent acinar cell dedifferentiation in pancreatitis and pancreatic cancer.

On the other hand, this cellular plasticity can be exploited for forced transdifferentiation towards endocrine beta-cells, the cell type that is destroyed in diabetes (type 1). Exocrine acinar and endocrine beta-cells have a common embryonic precursor. By the dedifferentiation of the acinar cells, they can be guided into the endocrine lineage. The latter was done with rat acinar cells that were converted into endocrine beta-cells by administration of specific growth factors and by interfering with the activated Notch pathway. This way a new source of beta-cells that can be used for replacement therapy, is discovered.

In conclusion, the results of this project are of use for the large group of diabetes patients and for the patients that suffer chronic pancreatitis and pancreatic cancer.

Ilse Rooman
Cell Differentiation Unit, Diabetes Research Center, Laarbeeklaan 103, B-1090 Brussels, Belgium
Tel:++32 2 477 4456; Fax: ++32 2 4774406; Email: irooman@vub.ac.be