Non-Tumor Ccaat/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation And Pancreatic Cancer Metastasis Formation

CCAAT/enhancer-binding protein delta (C/EBP delta) is a transcription factor involved in apoptosis and proliferation, which is downregulated in pancreatic ductal adenocarcinoma (PDAC) cells. Loss of nuclear C/EBP delta in PDAC cells is associated with decreased patient survival and pro-tumorigenic properties in vitro. Interestingly however, next to C/EBP delta expression in tumor cells, C/EBP delta is also expressed by cells constituting the tumor microenvironment and by cells comprising the organs and parenchyma. However, the functional relevance of systemic C/EBP delta in carcinogenesis remains elusive. Here, we consequently assessed the potential importance of C/EBP delta in somatic tissues by utilizing an orthotopic pancreatic cancer model. In doing so, we show that genetic ablation of C/EBP delta does not significantly affect primary tumor growth but has a strong impact on metastases; wildtype mice developed metastases at multiple sites, whilst this was not the case in C/EBP delta(-/-) mice. In line with reduced metastasis formation in C/EBP delta(-/-) mice, C/EBP delta-deficiency also limited tumor cell dissemination in a specific extravasation model. Tumor cell extravasation was dependent on the platelet-activating factor receptor (PAFR) as a PAFR antagonist inhibited tumor cell extravasation in wildtype mice but not in C/EBP delta(-/-) mice. Overall, we show that systemic C/EBP delta facilitates pancreatic cancer metastasis, and we suggest this is due to C/EBP delta-PAFR-dependent tumor cell extravasation.