The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non-cell-autonomous mechanisms

Developmental genes contribute to cancer, as reported for the homeobox gene playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in expression belong to the serrated subtype with the worst evolution. In mice, mosaic knockout of in the adult intestinal epithelium induces the formation of imperfect gastric-type metaplastic lesions. The metaplastic knockout cells do not spontaneously become tumorigenic. However, they induce profound modifications of the microenvironment that facilitate the tumorigenic evolution of adjacent -intact tumor-prone cells at the surface of the lesions through NF-κB activation, induction of inducible nitric oxide synthase, and stochastic loss of function of This study presents a novel paradigm in that metaplastic cells, generally considered as precancerous, can induce tumorigenesis from neighboring nonmetaplastic cells without themselves becoming cancerous. It unveils the novel property of non-cell-autonomous tumor suppressor gene for the gene in the gut.