CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells.

Simple Summary Here we show that a protein called C/EBP delta is present in healthy pancreas tissue but almost absent in pancreas tumors. Patients with less C/EBP delta in their tumors had the most metastases and the worst survival chances, showing that C/EBP delta has tumor-suppressive properties in pancreatic cancer. In this study, we reactivated C/EBP delta in pancreatic cancer cellsin vitroand observed a reduction in cell proliferation in a 2-dimentional and 3-dimensional space. This implies that tumor cells grow slower when C/EBP delta is activated and they are likely also less capable to escape the primary tumor in order to form metastases. Conversely, when we deleted C/EBP delta in pancreatic cancer cells, we observed accelerated growth. We suggest that reactivating C/EBP delta can suppress tumor growth and formation of metastases, thereby improving patient survival. CCAAT/enhancer-binding protein delta (C/EBP delta) is a transcription factor involved in growth arrest and differentiation, which has consequently been suggested to harbor tumor suppressive activities. However, C/EBP delta over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic role of C/EBP delta in these contexts. Here, we explore the role of C/EBP delta in pancreatic cancer. We determined C/EBP delta expression in biopsies from pancreatic cancer patients using public gene-expression datasets and in-house tissue microarrays. We found that C/EBP delta is highly expressed in healthy pancreatic ductal cells but lost in pancreatic ductal adenocarcinoma. Furthermore, loss of C/EBP delta correlated with increased lymph node involvement and shorter overall survival in pancreatic ductal adenocarcinoma patients. In accordance with this, in vitro experiments showed reduced clonogenic capacity and proliferation of pancreatic ductal adenocarcinoma cells following C/EBP delta re-expression, concurrent with decreased sphere formation capacity in soft agar assays. We thus report a previously unrecognized but important tumor suppressor role of C/EBP delta in pancreatic ductal adenocarcinoma. This is of particular interest since only few tumor suppressors have been identified in the context of pancreatic cancer. Moreover, our findings suggest that restoration of C/EBP delta activity could hold therapeutic value in pancreatic ductal adenocarcinoma, although the latter claim needs to be substantiated in future studies.