Abstract 645: Impact of sex differences on cross-talk between the gut microbiome, CEACAMs, and TGF-β signaling in cancers

Abstract

Abstract Background: Sex differences, microbiome alterations and obesity are prominent factors modulating gastrointestinal (GI) cancers, such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, there is a limited understanding of the interactions between intestinal epithelial and immune cells that participate in the regulation of the microbiome and the prevention or promotion of inflammation and the development of cancer. CEACAM proteins are immune and epithelial cell regulators, and some CEACAMs (CEACAM1, 3, 5, and 6) bind to pathogenic microbes. CEACAMs and mutations of the encoding genes are potential drivers of microbiome changes through altered regulation of host-immune response, through a mechanism that we hypothesize involves TGF-β signaling. We found that genetic alterations in CEACAM-encoding genes correlate with scores of TGF-β pathway activity in GI cancers in The Cancer Genome Atlas (TCGA). Furthermore, nearly 40% of human GI cancers have genetic alterations in components and regulators of the TGF-β pathway. We, therefore, investigated crosstalk between pathogen-binding CEACAM1, the gut microbiome, and the multifunctional intrinsically disordered protein βII-spectrin (SPTBN1), a Smad3 adaptor in driving CRC and liver cancers. Methods: The DNA from fecal samples collected from wild-type mice or TGF-β signaling-deficient mice Smad4+/-Sptbn1+/- were analyzed through shotgun metagenomics sequencing to identify changes in gut microbiota composition. We examined CEACAM expression, changes in the T cell populations, liver inflammation, and cancer in tissues from liver-specific βII-spectrin knockout (LSKO) mice fed a Western diet. Results: Mice heterozygous for the Sptbn1 gene (Sptbn1+/-) combined with heterozygosity of Smad4 (Smad4+/-Sptbn1+/-) spontaneously developed GI cancers, in the C57BL/6J genetic background. These mice exhibit an increased bacterial species associated with CRC in humans (C. septicum) and decreased commensal gut microbes associated with a healthy microbiome (B. vulgatus, P. distasonis). In addition, male Sptbn1+/- mice spontaneously developed HCC and showed reduced regulatory T (Treg) cells, whereas female mice did not, suggesting that βII-spectrin has a role in immune cell homeostasis that may affect tumor suppression. Single cell analyses revealed that Ceacam1 expression decreases in hepatocytes in mice fed a Western diet. CEACAM1 levels are restored to normal in tissues from liver-specific βII-spectrin knockout (LSKO) mice. Furthermore, we observed diet-induced changes in the T cell populations, liver inflammation, and cancer are also blocked in LSKO mice. Conclusion: Our study highlights how two critical pathways, TGF-β signaling and immune mediators CEACAM1 and 5, can drive inflammation and cancer through microbiome alterations with host sex having marked impact on the relevant signaling pathways. Citation Format: Krishanu Bhowmick, Addison Klebanov, Sahara John, Xiaochun Yang, Xiyan Xiang, Anil Vegesna, Kazufumi Ohshiro, James M. Crawford, Nicole Beauchemin, Raja Mazumder, Keith A. Crandall, Lopa Mishra. Impact of sex differences on cross-talk between the gut microbiome, CEACAMs, and TGF-β signaling in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 645.