1999/12/18 by H. Ferguson · 7 citations
Social Sciences · Biochemistry, Genetics and Molecular Biology · #Tattoo and Body Piercing Complications #Venomous Animal Envenomation and Studies
paper · doi:10.1136/bmj.319.7225.1627
openalex publication_date 1999/12/18 · openalex created_date 2022/05/12 · openalex updated_date 2026/07/30
<h3>Background</h3> Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for <i>Kras<sup>G12D</sup></i>-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer. <h3>Methods</h3> We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in <i>Pdx1-cre;LSL-Kras<sup>G12D</sup>;Ink4a/Arf<sup>fl/fl</sup></i>(<i>KIC</i>) mice. <h3>Results</h3> Even in the context of the second tumorigenic hit of <i>Ink4a/Arf</i> deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of <i>KIC</i> pancreas. Only half of <i>Nupr1</i>-deficient;<i>KIC</i> mice achieved PDAC development, and incident cases survived longer than <i>Nupr1<sup>wt</sup>;KIC</i> mice. This was associated with the development of well-differentiated PDACs in <i>Nupr1</i>-deficient;<i>KIC</i> mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. <i>Nupr1</i>-deficient;<i>KIC</i> PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, <i>Nupr1<sup>wt</sup>;KIC</i> mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from <i>Nupr1-</i>deficient;<i>KIC</i> PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with <i>Nupr1<sup>wt</sup>;KIC</i> cells. Moreover, <i>Nupr1</i>-deficient and <i>Nurpr1<sup>wt</sup>;KIC</i> 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. <h3>Conclusions</h3> According to <i>Nupr1</i> status, <i>KIC</i> mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials.