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Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis
  1. Carla E Cano1,
  2. Tewfik Hamidi1,
  3. Maria Noé Garcia1,
  4. Daniel Grasso1,
  5. Céline Loncle1,
  6. Stéphane Garcia1,
  7. Ezequiel Calvo2,
  8. Gwen Lomberk3,4,
  9. Nelson Dusetti1,
  10. Laurent Bartholin5,
  11. Raul Urrutia3,4,
  12. Juan L Iovanna1
  1. 1Centre 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
  2. 2Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, Canada
  3. 3Laboratory of Epigenetics and Chromatin Dynamics, Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Division of Gastroenterology and Hepatology, Rochester, Minnesota, USA
  4. 4Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
  5. 5INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Lyon, France
  1. Correspondence to Dr Juan L Iovanna, 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, 163 Av de Luminy, Campus de Luminy, Marseille 13288, France; juan.iovanna{at}


Background Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for KrasG12D-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-KrasG12D;Ink4a/Arffl/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 Nupr1wt;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, Nupr1wt;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 Nupr1wt;KIC cells. Moreover, Nupr1-deficient and Nurpr1wt;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.


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