SMAD4 and pancreatic neoplasm: Interestingly, in pancreatic canceroids derived from 25 genetically different biopsies, SMAD4 mutation enables CCM through SMAD4-independent non-canonical TGF-beta signalling and its downstream targets of RAC1 and CDC42, whereas without SMAD4 mutation, the pancreatic cancer cells exhibit mesenchymal migration [22] (Figure 2A).