Targeting the Wnt pathway in colorectal tumorigenesis

▸ Valenta T, Degirmenca B, Moor AE, et al. Wnt Ligands secreted by subepithelial mesenchymal cells are essential for the survival of intestinal stem cells and gut homeostasis. Cell Reports 2016;15:911–18.

Dysregulation of the Wnt signalling pathway is crucial for the development of intestinal tumorigenesis and stem cells require a precise concentration of available Wnt to maintain the intestinal epithelium. The authors of this manuscript suggest that targeting inappropriate Wnt signalling may be a strategy to prevent or to treat colorectal cancer. To investigate the effects of globally inhibiting Wnt secretion and determining the effect of this on intestinal homoeostasis, the authors conditionally knocked out the Wntless (Wls) gene (Wls^CKO). Wls facilitates Wnt secretion. Knocking out Wnt signalling genes such as Tcf4, has a profound effect on the stem cell population dramatically decreasing cell numbers. Conditionally knocking out β-catenin has a similar effect. Paneth cells have been proposed to act as niche cells supporting stem cell homoeostasis through the production of Wnt ligands. It is known that knocking out Paneth cells in organoids results in their death, however this has been predominantly tested in epithelial-only systems and we do not know the effective contribution of Wnt from other cells including stromal cells. Here the authors show that stem cell loss was maintained if Wls were knocked out in epithelial cells, and when exogenous Wnt2b was supplied to Wls^CKO mice or Wls^CKO organoids, suggesting that Paneth cells are capable of maintaining crypt homoeostasis, but they are not essential for it. To determine which non-epithelial cells can perform this function, the authors performed in situ hybridisation for Wnt2b and Wnt5a in conjunction with Acta2 (smooth muscle actin-α expressed by myofibroblasts and smooth muscle cells) and demonstrated that both Acta2-positive and Acta2-negative cells surrounding crypts are capable of producing …