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A genetically engineered mouse model developing rapid progressive pancreatic ductal adenocarcinoma
Takashi Yamaguchi1, Sanae Ikehara, Hayao Nakanishi
1Molecular Medicine Team, Research Centre for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan.
The Journal of Pathology
|July 22, 2014
Summary
SV40 large T antigen (TAg) synergistically promotes Kras(G12D)-driven pancreatic ductal adenocarcinoma (PDAC) formation in a new mouse model. This study offers insights into PDAC carcinogenesis mechanisms.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) development involves mutations in KRAS and alterations in Rb-E2F and MDM2-p53 pathways.
- The viral oncoprotein SV40 large T antigen (TAg) can disrupt these critical cellular pathways.
Purpose of the Study:
- To investigate if the viral oncoprotein TAg promotes pancreatic duct carcinogenesis initiated by oncogenic KRAS.
- To establish a novel mouse model for studying PDAC development.
Main Methods:
- Generated mice with pancreas-specific expression of temperature-sensitive SV40 large T antigen (tsTAg), with and without oncogenic Kras(G12D).
- Analyzed tumor development, histology, and gene transcription (E2f, Sre) in response to tsTAg and Kras(G12D).
Main Results:
- Pancreas-specific tsTAg expression led to acinar cell dysplasia but not PanIN.
- Co-expression of tsTAg and Kras(G12D) rapidly induced aggressive, ductal adenocarcinoma resembling human PDAC.
- Oncogenic Kras and tsTAg synergistically activated E2f and Sre transcription in PDAC cell lines.
Conclusions:
- SV40 TAg synergistically enhances Kras(G12D)-driven PDAC formation.
- This study introduces a valuable mouse model for understanding PDAC carcinogenesis and its aggressive clinical course.
