Abstract 6953: Wnt2b deficiency exacerbates colitis and leads to increased tumorigenesis in mice

Abstract

Abstract Colitis-associated cancer (CAC) is considered the most severe complication of inflammatory bowel disease (IBD). It has been demonstrated that WNT2B deficiency leads to severe intestinal impairment in humans and predisposes to colitis in mice. Evaluating a human cohort from The Cancer Genome Atlas (TCGA), we observed that low expression of WNT2B is associated with poor prognosis of patients with colon cancer. However, the functional roles of WNT2B in CAC development remain unclear, and we hypothesized that WNT2B is involved in the resistance to CAC development during long-term colitis. Thus, we model CAC development using Wnt2b deficient mice subjected to mutagenesis induction with 10 mg/kg Azoxymethane (AOM) and a long-term colitis protocol with three cycles of 2.5% Dextran Sodium Sulfate in the drinking water for three days, followed by a recovery period with autoclaved water. We observed that Wnt2b KO mice had increased susceptibility to colitis and more significant body weight changes than WT mice, especially in the first and second recovery cycles of colitis recovery. The maximum weight loss and disease activity index (DAI) were significantly higher in KO than in WT mice. Interestingly, Wnt2b KO mice developed more tumors, which were more extensive than those observed in WT. Moreover, the histopathological analysis showed that Wnt2b KO had the highest score for ulceration, aberrant crypt foci, and immune cell infiltration. Our data suggest a protective role for WNT2B, conferring resistance to tumor development during colitis. Furthermore, our data provides new insights into the functional roles of Wnt ligands in colon cancer. A better understanding of the factors involved in CAC etiology is critical for improving diagnosis and developing new targeted therapies. We believe WNT2B may emerge as one of these factors and offer novel targets for improved colorectal cancer management. Citation Format: Luiz Fernando Silva Oliveira, Amy E. O'Connell. Wnt2b deficiency exacerbates colitis and leads to increased tumorigenesis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6953.