Abstract
Pancreatic cancer is the fourth leading course of cancer death and early detection of the disease is crucial for successful treatment. However, pancreatic cancer is difficult to detect in its earliest stages and once symptoms appear, the cancer has often progressed beyond possibility for curing. Research into the disease has been hampered by the lack of good models. We have generated a porcine model of pancreatic cancer with use of transgenic overexpression of an oncogene cassette containing MYC, KRAS G12D and SV40 LT. The expression was initiated from a modified Pdx-1 promoter during embryogenesis in a subset of pancreatic epithelial cells. Furthermore, cells expressing the oncogenes also expressed a yellow fluorescent protein (mVenus) and an inducible negative regulator protein (rtTR-KRAB). Cells where the Pdx-1 promoter had not been activated, expressed a red fluorescent protein (Katushka). In vitro analyses of cells obtained from the transgenic pigs showed increased proliferation and expression of the transgenes when activated. Induction of the repressor protein eliminated the oncogene expression and decreased cell proliferation. In vivo analysis identified foci of pancreatic cells expressing the oncogenes at day zero post farrowing. These populations expanded and formed hyperplastic foci, with beginning abnormality at day 45. Cells in the foci expressed the oncogenic proteins and the majority of the cells were positive for the proliferation marker, Ki67. We predict that this model could be used for advanced studies in pancreatic cancer in a large animal model with focus on early detection, treatment, and identification of new biomarkers.
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Acknowledgements
The technical assistance of Mohammad Baragji and the input from Ernst-Martin Füchtbauer is greatly appreciated. We thank Janne Adamsen, Ruth Kristensen, Anette M. Pedersen, and Klaus Villemoes for expert technical assistance regarding blastula/morula production. The work was funded by Lundbeck and the Danish Council for Independent Research, Aage og Johanne Louis-Hansen’s fund, Fabricant Einar Willumsens memorial fund, Director Emil C. Hertz and wife Inger Hertz’s fund, and Karen Elise Jensen’s fund. J.E.J was supported by the Danish Agency for Science, Technology, and Innovation. M.K.T. was funded by a DFF-Mobilex postdoc fellowship funded through the EU 7th frame program and Aarhus University Research Foundation.
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Jannik E. Jakobsen and Martin K. Thomsen have equally contributed to this work.
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Berthelsen, M.F., Callesen, M.M., Østergaard, T.S. et al. Pancreas specific expression of oncogenes in a porcine model. Transgenic Res 26, 603–612 (2017). https://doi.org/10.1007/s11248-017-0031-4
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DOI: https://doi.org/10.1007/s11248-017-0031-4