Alternative splicing generates two isoforms of the transcription factor paired-related homeobox 1 (PRRX1): PRRX1a and PRRX1b. Takano et al. show that in pancreatic ductal adenocarcinoma (PDAC), both isoforms have distinct roles in metastasis. Both in vitro and in PDAC mouse models, PRRX1b promotes epithelial–mesenchymal transition, invasion and tumour de-differentiation, whereas PRRX1a promotes the reverse mesenchymal–epithelial transition, differentiation and metastatic growth in the liver. Evidence of a similar PRRX1 switch was also observed in human PDAC samples. One transcriptional target of PRRX1b was the hepatocyte growth factor gene (Hgf), and inhibition of HGF in combination with gemcitabine reduced tumour growth and metastasis in an orthotopic PDAC mouse model.