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Nuclear protein (Nupr)-1 is required for pancreatic adenocarcinoma development in Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl mice

ABSTRACT: Nuclear Protein 1 (Nupr1) is a major actor of the cell stress response required for KrasG12D-driven formation of pancreatic intraepithelial neoplastic (PanINs) lesions in mice. We investigated the impact of Nupr1-depletion on the development and biology of murin pancreatic adenocarcinomas (PDAC) in the Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mice. We found that only one half of Nupr1-deficient mice developed PDAC. This is related to increased caspase 3 activity and low IER3 expression in Nupr1-deficient;KIC in the pancreas. Moreover, when Nupr1-deficient;KIC mice do develop PDAC, tumors present with impaired epithelial-to-mesenchymal transition (EMT). Transcriptoma analysis revealed that Nupr1-deficient and Nupr1wt;KIC PDACs presented enrichment of gene signatures of the human classical- and quasi-mesenchymal (QM)-PDAC respectively. Moreover, Nupr1-deficient;KIC PDACs shared with human classical-PDACs overexpression of Kras-activation genes. In addition, cells derived from Nupr1-deficient;KIC PDACs formed fewer microspheres in vitro compared to Nupr1wt;KIC cells, indicative of stemness impairment in the absence of Nupr1. Finally, we found that Nupr1-deficient;KIC cells were more sensitive to some anticancer drugs than their Nupr1wt counterpart. Hence, this study establishes the pivotal role of Nupr1 in PDAC progression after PanIN and in PDAC EMT in vivo, with an impact in PDAC cell stemness. As a consequence, according to absence or presence of Nupr1, KIC mice develop tumors that phenocopy human classical- or QM-PDAC, respectively, thus becoming attractive models for preclinical drug trials.

ORGANISM(S): Mus musculus

PROVIDER: GSE42322 | GEO | 2012/12/16

SECONDARY ACCESSION(S): PRJNA181024

REPOSITORIES: GEO

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Project description:The objective of this study was to elucidate the role of Nupr1 in pancreatic tumorigenesis. Using the Pdx-1-cre;LSL-KrasG12D mouse as model we discovered that, in contrast to KrasG12D pancreas that develop multiple foci of pancreatic intraepithelial neoplasia (PanIN), KrasG12D;Nupr1KO pancreas were free from such lesions, indicating that Nupr1 is pivotal for PanIN formation. In vitro, MiaPaCa2 cells activated Nupr1 expression in response to nutrient deprivation and this expression was necessary for cell survival. Mechanistically, Nupr1 protected cells from stress-induced death by inhibiting apoptosis through an alternative RelBàIER3-dependent pathway and independent from activation of the classical RelA-based NF-kB pathway. In agreement with these findings, Nupr1, RelB and IER3 proteins were found co-expressed in PanINs from KrasG12D pancreas. Moreover, pancreas-specific KrasG12D;RelbDpanc mice displayed a delay in PanIN development associated with a lack of IER3 expression, further emphasizing the relevance of this pathway in vivo. Efficient PanIN formation was therefore dependent on the expression of Nupr1 and RelB, with the probable involvement of IER3. Finally, a significant correlation between expression of Nupr1, RelB and IER3 and a poor prognosis of patients with PDAC was found. Altogether, our results reveal a novel stress-related pathway that requires the functional interaction of Nupr1àRelBàIER3 in KrasG12D-dependent transformation of the pancreas and expand our understanding of the molecular machinery that mediates the early steps of pancreatic carcinogenesis. Since Nupr1 belongs to the HMG family of chromatin remodelers with transcriptional co-factor activity, Nupr1 could increase cell survival in a nutrient-deprived microenvironment by activating the expression of pro-survival genes. Moreover, considering that RelB, and not RelA/p65, is essential to the Nupr1-mediated survival mechanism that takes place upon nutrient deprivation-induced stress, we made the hypothesis that the two NF-kB transcription factors should activate different sets of genes among which a pivotal pro-survival gene would be exclusively dependent on RelB. In order to test this two hypothesis, an Affymetrix microarray analysis was performed using pancreatic cancer cells transfected with siCtrl or siNupr1 and cultured for 3, 6 or 9 hrs in EBSS; or transfected with siRelB, siRelA/p65 or siCtrl and cultured for 9 hrs in EBSS or Mock.

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Nuclear protein (Nupr)-1 is required for pancreatic adenocarcinoma development in Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl mice

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