title: Pancreas-specific activation of mTOR and loss of p53 induce tumors reminiscent of acinar cell carcinoma.
abstract: BACKGROUND
  Pancreatic acinar cell carcinoma (ACC) is a rare tumor entity with an unfavorable prognosis. Recent whole-exome sequencing identified p53 mutations in a subset of human ACC. Activation of the mammalian target of rapamycin (mTOR) pathway is associated with various pancreatic neoplasms. We thus aimed at analyzing whether activation of mTOR with a concomitant loss of p53 may initiate ACC.
  
  
  METHODS
  We generated transgenic mouse models in which mTOR was hyperactivated through pancreas-specific, homozygous tuberous sclerosis 1 (Tsc1) deficiency, with or without deletion of p53 (Tsc1 (-/-) and Tsc1 (-/-) ; p53 (-/-) ). Activity of mTOR signaling was investigated using mouse tissues and isolated murine cell lines. Human ACC specimens were used to corroborate the findings from the transgenic mouse models.
  
  
  RESULTS
  Hyperactive mTOR signaling in Tsc1 (-/-) mice was not oncogenic but rather induced a near-complete loss of the pancreatic acinar compartment. Acinar cells were lost as a result of apoptosis which was associated with p53 activation. Concomitantly, ductal cells were enriched. Ablation of p53 in Tsc1-deficient mice prevented acinar cell death but promoted formation of acinar cells with severe nuclear abnormalities. One out of seven Tsc1 (-/-) ; p53 (-/-) animals developed pancreatic tumors showing a distinctive tumor morphology, reminiscent of human ACC. Hyperactive mTOR signaling was also detected in a subset of human ACC.
  
  
  CONCLUSIONS
  Hyperactive mTOR signaling combined with loss of p53 in mice induces tumors similar to human ACC.
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Chengjia
authors.initials: C
authors.lastname: Qian
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Institute of Pathology, TUM, Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Cao
authors.affiliation: Institute of Pathology, TUM, Munich, Germany.
authors.forename: Anna Melissa
authors.initials: AM
authors.lastname: Schlitter
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Regel
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Raulefs
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.|Department of Surgery, Koc School of Medicine, Istanbul, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Institute of Pathology, TUM, Munich, Germany.|Institute of Pathology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.|Royal Liverpool and Broadgreen University Hospitals, Liverpool, UK.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.affiliation: Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. cwmichalski@gmail.com.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Michalski
mesh_terms: D000818:Animals; D017209:Apoptosis; D018267:Carcinoma, Acinar Cell / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases