Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is often metastatic upon the initial diagnosis, and has a high mortality rate. However, the primary and the matched metastatic cancers often share the same driver gene mutations. Gene expression comparison between primary and metastatic PDAC tissues revealed high expression of Gli2 and YAP1 in the metastatic PDAC. Gli2 is an important player in non-canonical hedgehog signaling, and YAP1 is an essential cell polarity gene. In this study, we investigated the effects of Gli2 and YAP1 on pancreatic cancer cell function in 3D culture and in mouse models. We further determined the relationship between Gli2 and YAP1. These studies further our understanding of pancreatic cancer metastasis.