title: Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition.
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.
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Ronan
authors.initials: R
authors.lastname: Russell
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Perkhofer
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Oesterbergstr. 3, Tuebingen 72074, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Department of Cell Biology, Institute for Biomedical Engineering, Medical Faculty, RWTH Aachen University, Pauwelstr. 30, Aachen 52074, Germany.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.affiliation: Institute of Pathology, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Fenja M
authors.initials: FM
authors.lastname: Feld
authors.affiliation: Department of Gastroenterology II, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hessmann
authors.affiliation: Department of Surgery, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Güthle
authors.affiliation: Department of Cell Biology, Institute for Biomedical Engineering, Medical Faculty, RWTH Aachen University, Pauwelstr. 30, Aachen 52074, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
authors.affiliation: Department of Surgery, Technische Universität München, Ismaninger Str. 22, Munich 81675, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartmann
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, Munich 81675, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: von Figura
authors.affiliation: Institute of Pathology, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Weissinger
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V., Beutenbergstr. 11, Jena 07745, Germany.
authors.forename: Karl-Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.affiliation: Institute of Pathology, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.affiliation: Institute of Pathology, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)