Regulation of pancreas plasticity and malignant transformation by Akt signaling.

Elghazi L, Weiss AJ, Barker DJ, Callaghan J, Staloch L, Sandgren EP, Gannon M, Adsay VN, Bernal-Mizrachi E
Gastroenterology. 2009 136 (3): 1091-103

PMID: 19121634 · PMCID: PMC2739876 · DOI:10.1053/j.gastro.2008.11.043

BACKGROUND & AIMS - Extensive evidence suggests that Akt signaling plays an important role in beta-cell mass and function, although its function in the regulation of the different pancreatic fates has not been adequately investigated. The goal of these studies was to assess the role of Akt signaling in the pancreatic differentiation programs.

METHODS - For these experiments, we have generated a double reporter mouse model that provides activation of Akt signaling in a cell type-specific manner. This mouse model conditionally overexpresses a constitutively active form of Akt upon Cre-mediated recombination. Activation of Akt signaling in pancreatic progenitors and acinar and beta-cells was achieved by crossing this animal model to specific Cre-lines.

RESULTS - We showed that overexpression of a constitutively active Akt in pancreatic and duodenal homeobox 1 (Pdx1) progenitors induced expansion of ductal structures expressing progenitor markers. This expansion resulted in part from increased proliferation of the ductal epithelium. Lineage-tracing experiments in mice with activation of Akt signaling in mature acinar and beta-cells suggested that acinar-to-ductal and beta-cell-to-acinar/ductal transdifferentiation also contributed to the expansion of the ductal compartment. In addition to the changes in cell plasticity, these studies demonstrated that chronic activation of Akt signaling in Pdx1 progenitors induced the development of premalignant lesions and malignant transformation in old mice.

CONCLUSIONS - The current work unravels some of the molecular mechanisms of cellular plasticity and reprogramming, and demonstrates for the first time that activation of Akt signaling regulates the fate of differentiated pancreatic cells in vivo.

MeSH Terms (19)

Animals Cell Differentiation Cell Division Cell Transformation, Neoplastic Epithelial Cells Genes, Reporter Glucose Homeodomain Proteins Insulin-Secreting Cells Integrases Mice Mice, Transgenic Pancreas Pancreatic Ducts Pancreatic Neoplasms Proto-Oncogene Proteins c-akt Signal Transduction Stem Cells Trans-Activators

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