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Nat Commun. 2015 Jul 29;6:7677. doi: 10.1038/ncomms8677.

Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition.

Author information

1
Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
2
Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Oesterbergstr. 3, Tuebingen 72074, Germany.
3
Department of Cell Biology, Institute for Biomedical Engineering, Medical Faculty, RWTH Aachen University, Pauwelstr. 30, Aachen 52074, Germany.
4
Institute of Pathology, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
5
Department of Gastroenterology II, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany.
6
Department of Surgery, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany.
7
Department of Surgery, Technische Universität München, Ismaninger Str. 22, Munich 81675, Germany.
8
II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, Munich 81675, Germany.
9
Leibniz Institute for Age Research - Fritz Lipmann Institute e.V., Beutenbergstr. 11, Jena 07745, Germany.

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.

PMID:
26220524
PMCID:
PMC4532798
DOI:
10.1038/ncomms8677
[Indexed for MEDLINE]
Free PMC Article

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