The role of Notch as a crucial determinant of tumour cell phenotype is consistent with its established role in liver development, as previously emphasised, where hepatoblast differentiation is dependent upon the cell’s location relative to the portal vein mesenchyme and hence exposure to the Notch ligand JAG1, as well as other signals including TGFβ.40 Evidence from mouse studies suggest that Notch activation can be a key driver of CC development, regardless of the cell of origin in which the initiating mutational events occur (Fig. 3). Here, TGFB1 is linked to cholangiocarcinoma.