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Genetic and pharmacologic abrogation of Snail1 inhibits acinar-to-ductal metaplasia in precursor lesions of pancreatic ductal adenocarcinoma and pancreatic injury

Oncogene volume 37, pages 1845–1856 (2018)Cite this article

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Abstract

Pancreatic cancer (PDAC) is one of the most dismal of human malignancies. Inhibiting or delaying the progression of precursor lesions of PDAC, pancreatic intraepthial neoplasia (PanINs), to invasive cancer, would be a major step. In the present study, we used a transgenic murine model of pancreatic cancer to evaluate the impact of a conditional knockout of the transcription factor Snail1, a major factor in epithelial-to-mesenchymal transition, on acinar-to-ductal formation and on PanIN progression. By interbreeding conditional LsL-Snailfloxf/wt; LsL-KrasG12D and Pdx1-Cre strains, we obtained LsL-KrasG12D;Pdx1-Cre(KP) mice, Snail1 heterozygous knockout LsL-KrasG12D; LsL-Snailflox/-;Pdx1-Cre(KPShet) mice or Snail1 homozygous knockout LsL-KrasG12D;LsL-Snailflox/flox;Pdx1-Cre(KPS) mice. Mice were then followed in a longitudinal study for 2, 4, 6, 8, 10, and 12 months. Furthermore, in mice with a genetic or pharmacological inhibition of Snail1, using the Snail1 inhibitor GN25, a model of pancreatic injury by administration of cerulein was introduced to evaluate ADM formation in this setting. A translational approach with a tissue microarray (TMA) of human PanINs and an in vivo nude mouse platform to test GN25 in human pancreatic adenocarcinoma was then adopted. Quantification of PanINs showed delayed initiation and progression of PanIN lesions at all ages in both homozygous and heterozygous Snaildel1;Pdx-1-Cre;LSL-KrasG12D/+-Mice. PanINs at TMA revealed snail expression in the majority of cases. GN25 showed growth inhibition in 2/2 human pancreatic adenocarcinomas using a nude mice in vivo platform. Genetic and pharmacologic abrogation of Snail1 signaling in exocrine pancreas impairs development of acinar-to-ductal metaplasia following cerulein-mediated pancreatic injury. The present study suggests a fundamental new approach to delay the progression of PDAC.

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Acknowledgements

Grant support: VF and ML were supported by a Research Grant from the Sander Stiftung

Author contributions

VF: Study concept and design, obtained funding, analysis and interpretation, drafting manuscript, FJ: acquisition of data, critical revision of the manuscript. SB: Acquisition of data, analysis. MA: Acquisition of data. ML: Obtained funding, technical support, acquisition of data, critical revision of the manuscript. FE: Technical support, acquisition of data. KH: Acquisition of data. JD: Acquisition of data. EPS: Critical revision of the manuscript for important intellectual content. JPNH: Critical revision of the manuscript for important intellectual content, AB: Acquisition of data. DKB: Critical revision of the manuscript for important intellectual content. JW: Study concept and design, analysis and interpretation, drafting the manuscript.

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Authors and Affiliations

  1. Department of Surgery, University of Marburg, Marburg, Germany

    Volker Fendrich, Frederike Jendryschek, Saskia Beeck, Max Albers, Janina Dengler, Emily P. Slater, Aninja Baier, Detlef K. Bartsch & Jens Waldmann

  2. IMT, Marburg, Germany

    Matthias Lauth

  3. Department of Surgery, John G. Rangos Research Center, University of Pittsburgh, Pittsburgh, PA, USA

    Farzad Esni

  4. Department of Internal Medicine, Division of Gastroenterology University Hospital Giessen and Marburg, Campus Marburg, Marburg, Germany

    Kristin Heeger

  5. Department of Surgery, University Hospital Giessen and Marburg, Campus Giessen, Giessen, Germany

    Julia P. N. Holler

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  1. Volker Fendrich
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Correspondence to Volker Fendrich.

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Fendrich, V., Jendryschek, F., Beeck, S. et al. Genetic and pharmacologic abrogation of Snail1 inhibits acinar-to-ductal metaplasia in precursor lesions of pancreatic ductal adenocarcinoma and pancreatic injury. Oncogene 37, 1845–1856 (2018). https://doi.org/10.1038/s41388-017-0100-4

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