Axin1 Protects Colon Carcinogenesis by an Immune-Mediated Effect.

Cellular and molecular gastroenterology and hepatology 2023

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Axin1 is a negative regulator of wingless-type MMTV integration site family, member 1 (Wnt)/β-catenin signaling with tumor-suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive. We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific, Axin1-knockout mice (Axin1ΔIEC) and Axin2-knockout mice. We evaluated the tumor-suppressor function of Axin1 during chemically induced colorectal tumorigenesis and dextran sulfate sodium-induced colitis, and performed comparative gene expression profiling by whole-genome RNA sequencing. The clinical relevance of the Axin1-dependent gene expression signature then was tested in a database of 2239 clinical colorectal cancer (CRC) samples. We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for Wnt pathway down-regulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced dextran sulfate sodium-induced colitis by attenuating the induction of a proinflammatory program. RNA-seq analyses identified an interferon γ/T-helper1 immune program controlled by Axin1 that enhances the inflammatory response and protects against CRC. The Axin1-dependent gene expression signature was applied to human CRC samples and identified a group of patients with potential vulnerability to immune checkpoint blockade therapies. Our study establishes, in vivo, that Axin1 has redundant function with Axin2 for Wnt down-regulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an interferon γ/Th1 program that prevents tumor growth. Linked to its T-cell-mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Romain Sanson, Silvia Luna Lazzara, David Cune, Caterina Luana Pitasi, Coralie Trentesaux, Marie Fraudeau, Franck Letourneur, Benjamin Saintpierre, Morgane Le Gall, Pascale Bossard, Benoit Terris, Pascal Finetti, François Bertucci, Emilie Mamessier, Béatrice Romagnolo, Christine Perret. Axin1 Protects Colon Carcinogenesis by an Immune-Mediated Effect. Cellular and molecular gastroenterology and hepatology. 2023;15(3):689-715