The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
Camille Balbinot (1), Olivier Armant (2), Nabila Elarouci (3), Laetitia Marisa (3), Elisabeth Martin (1), Etienne De Clara (1), Alina Onea (4), Jacqueline Deschamps (5), Felix Beck (6) ,Jean-Noël Freund (1), and Isabelle Duluc (1)
1 : Université de Strasbourg, Institut National de la Santé et de la Recherche Médicale, IRFAC UMR-S1113, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France
2 : Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Karlsruhe, Germany
3 : Cartes d’Identité des Tumeurs Program, Ligue Nationale Contre le Cancer, Paris, France
4 : Département de Pathologie, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France
5 : Developmental Biology and Stem Cell Research, Hubrecht Institute, Utrecht, Netherlands
6 : Barts and The London School of Medicine and Dentistry, London, England, UK
Developmental genes contribute to cancer, as reported for the homeobox gene Cdx2 playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in CDX2 expression belong to the serrated subtype with the worst evolution. In mice, mosaic knockout of Cdx2 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 Cdx2-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 Apc. 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 Cdx2 gene in the gut.