In acute and chronic pancreatitis, acinar cells of the pancreas are persistently inflamed and injured. Under normal conditions in mouse studies, these damaged cells rapidly regenerate, in a process that involves temporarily reactivating embryonic developmental molecular signals that allow the cells to regenerate. However, in acinar cells in which mutant Kras has been activated, the embryonic developmental signals remain active, keeping the cells in a so-called "de-differentiated" state, causing them to develop into cells that are precursors to PDA.
In the current study, reported in a recent issue of The Journal of Clinical Investigation (vol. 120, issue 2, 2010), the team set out to investigate how mutant Kras co-opts the damaged acinar cells.
The investigation, led by John P. Morris IV, a graduate student in the Hebrok lab, examined two sets of mice. One set of normal, or "control" mice, was chemically induced to have acute pancreatitis. Another set of mice was genetically engineered to carry a copy of the mutated, or overactive, Kras gene, and then induced to develop acute pancreatitis.
The scientists tracked the behavior, or "fate," of the fluorescently labeled acinar cells in both sets of mice. In the normal mice, the acinar cells transiently induced embryonic signaling and regenerated as expected. However, in the genetically engineered mice, the mutant Kras gene's protein, KRAS, blocked acinar cell regeneration and promoted persistently de-differentiated PDA precursor cells.
Probing for the molecular mechanism underlying this switch, the team discovered that the mutated KRAS blocked the action of a protein know as beta catenin. They also showed that beta catenin was required for efficient acinar regeneration. Most notably, they showed that when beta-catenin's signaling pathways were forcibly maintained in the context of the KRAS mutation, acinar cells did not become PDA precursor
|Contact: Jennifer OBrien|
University of California - San Francisco