Regulation of Pancreas Plasticity and Malignant Transformation by Akt Signaling

Lynda Elghazi, Aaron J. Weiss, Daniel J. Barker, John Callaghan, Lora Staloch, Eric P. Sandgren, Maureen Gannon, Volkan N. Adsay, Ernesto Bernal-Mizrachi

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Background & Aims: Extensive evidence suggests that Akt signaling plays an important role in β-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 β-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 β-cells suggested that acinar-to-ductal and β-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.

Original languageEnglish (US)
Pages (from-to)1091-1103.e8
JournalGastroenterology
Volume136
Issue number3
DOIs
StatePublished - Mar 2009

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'Regulation of Pancreas Plasticity and Malignant Transformation by Akt Signaling'. Together they form a unique fingerprint.

Cite this