CEACAM1 ALTERS TGF-β SIGNALING WITH AN ALTERED MICROBIOME DRIVING COLON CANCER

Background: Colon cancer is rising in younger people, with a potential link to diet and the gut microbiome. Yet, it is unclear how signaling pathways, host-microbe interactions and metabolites regulate cancer development. CEACAM1 in cells is implicated in tumorigenesis and increased in invasive colon cancer. CEACAM1 can respond to pathogenic microbes and it can interact with TGF-β/SPTBN1. Alterations in the TGF-β pathway occur in ~40% of human GI cancers, and mouse models with disrupted TGF-β signaling (Tgfbr2^-/-, Smad4^+/-Sptbn1^+/-, and Tgfb1^-/-) develop colorectal cancer (CRC) and an altered gut microbiome. Our previous studies indicate that lipid metabolites (reactive aldehydes) form toxic adducts with cleaved SPTBN1 and divert TGF-β to pro-oncogenic signaling. Similarly, metabolic dysregulation in primary CRCs is modulated by intestinal microbes and host/ microbial metabolites; elevated serum ammonia levels in patients with CRC are associated with poor prognosis. Thus, we hypothesize that “the intricate relationships among pathogen-binding CEACAM1, the gut microbiome, and βII-spectrin can drive colon cancer development”.
Methods: We examined gut microbiota composition, immune cell population, inflammation, and cancers in Smad4^+/-Sptbn1^+/- and Sptbn1^LSKO mice fed a normal chow diet or a high-fat diet (HFD). We evaluated the prognostic significance of high CEACAM1 expression and genetic alterations of TGF-β signaling in cancer patients through meta-analysis of datasets from the Cancer Genome Atlas (TCGA). We used Alphafold-based molecular modeling to analyze potential interaction sites between βII-spectrin and CEACAM1.
Results: CEACAM1 is known to interact with βII-spectrin (encoded by Sptbn1), and increased expression of CEACAM1 and βII-spectrin levels are associated with invasive human GI Cancers. We found strong correlations between impaired TGF-β signaling and genetic alterations in CEACAM-encoding genes in GI cancers from TCGA data analysis. Also, GI cancer patients with increased CEACAM1 expression had a poor prognosis and lower probability of survival. Mouse models with disrupted TGF-β signaling (Smad4^+/-Sptbn1^+/-) were found to display a unique gut microbiome signature compared to wild-type mice. Microbial metabolite ammonia induced CASPASE-3 mediated cleavage of βII-spectrin, formed toxic adducts and altered TGF-β signaling in cells to be more tumorigenic, triggering CRC. Intriguingly, βII-spectrin LSKO restored the gut microbiome and blocked inflammation and cancer.
Conclusion: We have found a critical role for CEACAMs in CRC cancer development by their ability to divert TGF-β signaling pathway to a pro-oncogenic phenotype. These studies indicate that CEACAM1, βII-spectrin, TGF-β, and the gut microbiome play critical roles in CRC development, and that βII-spectrin as well as CEACAM1 may be attractive therapeutic targets for CRC.