Engrailed-1 Promotes Pancreatic Cancer Metastasis

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, it is reported that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating roles in the activation of MAPK pathways and the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. The findings nominate the targeting of EN1 and downstream pathways in aggressive PDA. Metastatic pancreatic cancer exhibits aberrant expression of EN1, a critical homeodomain transcription factor for neuronal survival. EN1 predominantly represses its target genes by directly binding to their enhancers and promoters, implicating involvement in MAPK pathways and mesenchymal cell properties. Targeting EN1 and associated pathways may represent a promising strategy to exploit vulnerabilities in aggressive pancreatic cancer.image