We found that Nodal expression is upregulated widely in pancreatic cancer cells, not only in CSCs, but also in tumor-associated stromal cells, and it induces a metastatic phenotype in pancreatic cancer cells by promoting EMT and enhancing the expression of MMP2 and CXCR4 via the Smad2/3 pathway, indicating that Nodal signaling is a critical mechanism in the metastasis of pancreatic cancer and might be a therapeutic target for the treatment of pancreatic cancer. Here, CXCR4 is linked to familial pancreatic carcinoma.