Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras G12D , we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras G12D -expressing pancreas. Moreover, pancreasspecific deletion of Relb in a Kras G12D background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stressrelated pathway that is required for oncogenic Kras G12D -dependent transformation of the pancreas.
IntroductionPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate and the lowest overall survival of all cancers (less than 3%-4% at 5 years). The incidence of PDAC almost equals its mortality rate and is increasing every year, with more than 38,000 predicted new cases in the United States and 65,000 in Europe. Surgery is the most effective treatment, but the mean life expectancy of the 15%-20% of patients who present with a resectable tumor is only 15-18 months (1). Even for patients eligible for surgery, aggressive metastasis often appears after operation, and survival of patients with metastatic disease is only 3-6 months (2). Chemotherapy and radiotherapy offer limited benefit for patients undergoing surgery in metastatic disease (3). Most strategies tested so far for the treatment of PDAC have consisted of using therapies that show some efficacy in other carcinomas, but none of them improved significantly the overall survival of PDAC patients. Hence, in order to develop new, efficient therapies against PDAC, future research must take into account PDAC specificities such as its remarkable resistance to cell stress, notably to the stress induced by chemotherapy and radiotherapy (4), and the preponderant presence of a fibrotic stroma, which favors tumor progression by creating a barrier against drug delivery and