Regulation of pancreas plasticity and malignant transformation by Akt signaling.
OBJECTIVE
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.
Elghazi
Lynda
L
Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St Louis, Missouri, USA.
Weiss
Aaron J
AJ
Barker
Daniel J
DJ
Callaghan
John
J
Staloch
Lora
L
Sandgren
Eric P
EP
Gannon
Maureen
M
Adsay
Volkan N
VN
Bernal-Mizrachi
Ernesto
E
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology; D019426:Integrases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000166:cytology / Q000502:physiology*; D010183:Pancreatic Ducts / Q000166:cytology / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics
D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D051057:Proto-Oncogene Proteins c-akt; C045073:Cre recombinase; D019426:Integrases; D005947:Glucose