An epithelial Wnt-secreting niche drives inflammation induced colon carcinoma. Exome seuncing of AOM-DSS tumors and organoids

Colon cancer is initiated by stem cells that escape the strict control. In most colon tumors this process is driven through aberrant activation of Wnt signaling by mutations that occur in components acting downstream of the receptor complex and that unfetter tumor cells from the need for Wnt ligands. Here we describe a type of colon cancer that does not depend on mutated core components of the Wnt pathway, but on acquired Wnt-secretion. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells auto-secrete Wnt ligands to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt dependent colon cancer, that might be responsive to Wnt secretion inhibitors.