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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & S, 2015. "Loss of ATM accelerates pancreatic cancer formation and epithelial–mesenchymal transition," Nature Communications, Nature, vol. 6(1), pages 1-16, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8677
    DOI: 10.1038/ncomms8677
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