title: Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis.
abstract: BACKGROUND
  Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for Kras(G12D)-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer.
  
  
  METHODS
  We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in Pdx1-cre;LSL-Kras(G12D);Ink4a/Arf(fl/fl)(KIC) mice.
  
  
  RESULTS
  Even in the context of the second tumorigenic hit of Ink4a/Arf deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of KIC pancreas. Only half of Nupr1-deficient;KIC mice achieved PDAC development, and incident cases survived longer than Nupr1(wt);KIC mice. This was associated with the development of well-differentiated PDACs in Nupr1-deficient;KIC mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. Nupr1-deficient;KIC PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, Nupr1(wt);KIC mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from Nupr1-deficient;KIC PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with Nupr1(wt);KIC cells. Moreover, Nupr1-deficient and Nurpr1(wt);KIC cells differed in their sensitivity to the nucleoside analogues Ly101-4b and WJQ63. Together, these findings show the pivotal role of Nupr1 in both the initiation and late stages of PDAC in vivo, with a potential impact on PDAC cell stemness.
  
  
  CONCLUSIONS
  According to Nupr1 status, KIC mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials.
authors.affiliation: Centre de Recherche en Carcérologie de Marseille (CRCM), INSERM UMR 1068, CNRS UMR 7258, Aix-Marseille University and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, , Marseille, France.
authors.forename: Carla E
authors.initials: CE
authors.lastname: Cano
authors.forename: Tewfik
authors.initials: T
authors.lastname: Hamidi
authors.forename: Maria Noé
authors.initials: MN
authors.lastname: Garcia
authors.forename: Daniel
authors.initials: D
authors.lastname: Grasso
authors.forename: Céline
authors.initials: C
authors.lastname: Loncle
authors.forename: Stéphane
authors.initials: S
authors.lastname: Garcia
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Calvo
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.forename: Nelson
authors.initials: N
authors.lastname: Dusetti
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015820:Cadherins / Q000032:analysis; D063646:Carcinogenesis / Q000235:genetics*; D053148:Caspase 3 / Q000032:analysis; D002470:Cell Survival / Q000187:drug effects; D062445:Claudin-1 / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015870:Gene Expression; D016153:Genes, Suppressor / Q000502:physiology*; D006579:Heterozygote; D017874:Immediate-Early Proteins / Q000032:analysis; D008017:Life Expectancy; D051379:Mice; D018345:Mice, Knockout; D018396:Mucin-1 / Q000032:analysis; D009363:Neoplasm Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D015820:Cadherins; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D018396:Mucin-1; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D053773:Transforming Growth Factor beta1; C577056:muc1 protein, mouse; D003841:Deoxycytidine; D053148:Caspase 3; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine
keywords: CANCER; ONCOGENES; PANCREAS; PANCREATIC CANCER; STRESS