miR-21a-5p downregulation in M2 macrophage-derived EVs inhibited Nanog/Oct4 expression and impaired sphere-forming, colony-forming, invasion, migration, and anti-apoptosis abilities of PaCa stem cells in vitro and tumorigenic ability in vivo. Here, POU5F1 is linked to permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome.