Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis

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Abstract

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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