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

Author:

Balbinot Camille1,Armant Olivier2ORCID,Elarouci Nabila3ORCID,Marisa Laetitia3ORCID,Martin Elisabeth1,De Clara Etienne1,Onea Alina4,Deschamps Jacqueline5,Beck Felix6ORCID,Freund Jean-Noël1ORCID,Duluc Isabelle1

Affiliation:

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

Abstract

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.

Funder

Ligue Contre le Cancer

Fondation ARC pour la Recherche sur le Cancer

Institut National du Cancer

Ministère de l’Enseignement Supérieur et de la Recherche

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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