Figure 6.

Model of BMP–Notch interaction in intestinal homeostasis and CRC disease subtypes. In intestinal homeostasis, the BMP and Notch pathways are partially segregated. In the stem/progenitor zone at the base of the crypt, Notch signalling regulates intestinal stem cells and promotes progenitor cell division. Specific co‐localization of BMP and Notch signalling in cells emerging from the transit‐amplifying zone inhibits cell proliferation and promotes differentiation. In canonical tumours, loss of canonical BMP pathway constituents downregulates BMP signalling, promoting cell proliferation. In mesenchymal tumours, impaired pathway segregation, loss of SMAD1 and retention of SMAD5 enhance BMP–Notch interaction. In this model, BMP and Notch pathways act synergistically via a γ‐secretase‐independent mechanism to promote an EMT phenotype, which we postulate is promoted by the mesenchymal tumour microenvironment.