Deletion of NEMO Inhibits EMT and Reduces Metastasis in KPC Mice

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and is expected to be the second leading cause of cancer-related deaths in the USA by 2030. In the current study, we investigated the role of NEMO/NF-κB signaling in the development and metastasis of PDAC by using the genetically modified KPC mouse model. In the absence of NEMO, KPC mice exhibited extended survival, which was accompanied by a strong reduction in the development of liver metastasis and ascites. Our study provides evidence for a detrimental role of the conventional NF-κB pathway in the survival of KPC mice and underlines the fact that NF-κB could be a therapeutic target against PDAC. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a largely incurable cancer type. Its high mortality is attributed to the lack of efficient biomarkers for early detection combined with its high metastatic properties. The aim of our study was to investigate the role of NF-κB signaling in the development and metastasis of PDAC. We used the well-established KPC mouse model, and, through genetic manipulation, we deleted NF-κB essential modulator (NEMO) in the pancreata of KPC mice. Interestingly, NEMO deletion altered the differentiation status of the primary tumor but did not significantly affect its development. However, in the absence of NEMO, the median survival of the mice was prolonged by 13.5 days (16%). In addition, examination of the liver demonstrated that, whereas KPC mice occasionally developed liver macro-metastasis, NEMO deletion completely abrogated this outcome. Further analysis of the tumor revealed that the expression of epithelial–mesenchymal transition (EMT) transcription factors was diminished in the absence of NEMO. Conclusively, our study provides evidence that NF-κB is dispensable for the progression of high-grade PanINs towards PDAC. In contrast, NF-κB signaling is essential for the development of metastasis by regulating the gene expression program of EMT.