Oncomimetic β-catenin activity onset, duration and region defines aberrant intestinal development

In early intestinal carcinogenesis, adenoma formation is commonly initiated by loss-of-function mutations in a tumor suppressor that lead to oncoprotein gain-of-function, like in the tumor suppressor–oncoprotein pair APC–β-catenin. Small intestinal organoids provide an in vitro system to study consequences of such mutations on tissue organization. However, conventional genetic manipulations do not allow precise control over the onset and duration of oncoprotein activity to study their influence on tissue transformation. Furthermore, homogenous tissues of clonal genetic models do not readily capture cellular interaction among mutated and neighboring wildtype tissue during early transformation. To mimic oncogenic activation of β-catenin, we established a chemical-(opto)genetic approach to gain bio-orthogonal acute, spatial and temporal control over β-catenin oncoprotein stability and relate oncoprotein levels to morphological development of mouse small intestinal organoids.

We identified aberrant phenotypes that result from bio-orthogonally induced oncoprotein activity but persist even after oncoprotein depletion. Furthermore, local activation of oncomimetic β-catenin activity within the stem cell niche leads to aberrant differentiation during homeorhesis and homeostasis, recapitulating early events of tissue transformation.