Loss of ATM accelerates pancreatic cancer formation and epithelial–mesenchymal transition

Ronan Russell, Lukas Perkhofer, Stefan Liebau, Qiong Lin, André Lechel, Fenja M Feld, Elisabeth Hessmann, Jochen Gaedcke, Melanie Güthle, Martin Zenke, Daniel Hartmann, Guido von Figura, Stephanie E Weissinger, Karl-Lenhard Rudolph, Peter Möller, Jochen K Lennerz, Thomas Seufferlein, Martin Wagner () and Alexander Kleger ()
Additional contact information
Ronan Russell: Ulm University
Lukas Perkhofer: Ulm University
Stefan Liebau: Institute of Neuroanatomy, Eberhard Karls University
Qiong Lin: Institute for Biomedical Engineering, Medical Faculty, RWTH Aachen University
André Lechel: Ulm University
Fenja M Feld: Institute of Pathology, Ulm University
Elisabeth Hessmann: University Medical Center Goettingen
Jochen Gaedcke: University Medical Center Goettingen
Melanie Güthle: Ulm University
Martin Zenke: Institute for Biomedical Engineering, Medical Faculty, RWTH Aachen University
Daniel Hartmann: Technische Universität München
Guido von Figura: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München
Stephanie E Weissinger: Institute of Pathology, Ulm University
Karl-Lenhard Rudolph: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V.
Peter Möller: Institute of Pathology, Ulm University
Jochen K Lennerz: Institute of Pathology, Ulm University
Thomas Seufferlein: Ulm University
Martin Wagner: Ulm University
Alexander Kleger: Ulm University

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with accumulation of particular oncogenic mutations and recent genetic sequencing studies have identified ataxia telangiectasia-mutated (ATM) mutations in PDAC cohorts. Here we report that conditional deletion of ATM in a mouse model of PDAC induces a greater number of proliferative precursor lesions coupled with a pronounced fibrotic reaction. ATM-targeted mice display altered TGFβ-superfamily signalling and enhanced epithelial-to-mesenchymal transition (EMT) coupled with shortened survival. Notably, our mouse model recapitulates many features of more aggressive human PDAC subtypes. Particularly, we report that low expression of ATM predicts EMT, a gene signature specific for Bmp4 signalling and poor prognosis in human PDAC. Our data suggest an intimate link between ATM expression and pancreatic cancer progression in mice and men.

Date: 2015
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DOI: 10.1038/ncomms8677

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