Abstract 753: CEACAM1 induces microbiome and metabolite driven diversion of TGF-β signaling to promote colon cancer

Abstract

Abstract Background: Colon cancer is rising in younger individuals in the United States. Potential causal factors are altered diets and gut microbiomes. Yet key signaling pathways, host-microbe interactions, and metabolites such as ammonia in cancer remain unclear. CEACAM1 responds to pathogenic microbes, interacts with the TGF-β/SPTBN1 and levels are raised in invasive colon cancer. Alterations in the TGF-β pathway occur ~40% of human GI cancers, and mouse models with disrupted TGF-β signaling (Tgfbr2−/−, Smad4+/−Sptbn1+/−, and Tgfb1−/−) develop colorectal cancer (CRC) that is dependent upon an altered gut microbiome. Our previous studies indicate the lipid metabolites (reactive aldehydes) form toxic adducts with cleaved SPTBN1 and divert TGF-β signaling to pro-oncogenic process. Poor prognosis CRC is associated with raised levels of microbial metabolites, such as ammonia. Thus, we hypothesized that “the intricate relationships among pathogen-binding CEACAM1, the gut microbiome, metabolites such as ammonia, and βII-Spectrin drive colon cancer development”. Methods: We examined gut microbiota composition, immune cell population, inflammation, and cancers in Smad4+/−Sptbn1+/− and Sptbn1LSKO mice fed a normal chow diet or a high-fat diet (HFD). We evaluated CEACAM1 and TGF-β member alterations in in CRCs using TCGA datasets. Alphafold-based molecular modeling predicted interaction sites between βII-Spectrin and CEACAM1 was followed by functional studies. Results: Increased CEACAM1 levels with alterations in TGF-β members were associated with lower survival (TCGA). Mice with disrupted TGF-β signaling (Smad4+/−Sptbn1+/−) develop CRC, have high CEACAM1 levels, and an altered gut microbiome signature. CEACAM1 interacts with βII-Spectrin, and levels are restored to normal in βII-Spectrin LSKO which restores the gut microbiome and blocks inflammation and cancer. Ammonia induces CASPASE-3 mediated cleavage of βII-Spectrin, forms toxic adducts and divert TGF-β signaling to pathological pro-oncogenic signaling, triggering CRC. Conclusion: We have found a critical role for CEACAMs in CRC cancer development, through diverting the TGF-β signaling pathway to a pro-oncogenic phenotype. CEACAM1 and βII-Spectrin are attractive therapeutic targets for CRC. Citation Format: Krishanu Bhowmick, Kazufumi Ohshiro, Xiyan Xiang, Sahara John, Xiaochun Yang, Kevin Idicula, Nicole Beauchemin, Raja Mazumder, Keith A. Crandall, Mohammad I. Hassan, Taj Mohammad, Lopa Mishra. CEACAM1 induces microbiome and metabolite driven diversion of TGF-β signaling to promote colon cancer [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 753.