Rspo mutations skew intestinal secretory cell fate, enhance cell stemness and are preferentially selected in colitis-associated dysplasia

Mutation type varies from lesion to lesion, with different mutations preferentially acquired in different intestinal neoplasia subtypes. Here, we assessed the Wnt pathway mutation landscape across different sporadic and colitis-associated lesions to understand the variable capacity of different Wnt disrupting mutations to initiate neoplasia.

We then used mouse models to compare the impact of Apc (ligand-independent) and Rspo-overexpression (ligand-dependent) mutations on secretory and stem cell fate dynamics. In contrast with the effect of Apc mutation, which generates super-competing, niche seceding stem cells in sporadic disease, epithelial Rspo3 expression favours Paneth cell differentiation and supports the generation of new Wnt ligand-dependent intestinal stem cell niches.