SMAD4 mutation drives gut microbiome shifts toward tumor progression in colorectal cancer

Colorectal cancer (CRC) progression is driven by a series of sequential mutations in key driver genes; however, the factors underlying tumor progression and metastasis remain poorly understood. Mutations in TP53 and SMAD4, in particular, are associated with CRC progression. Although gut microbiome dysbiosis is implicated in CRC initiation and progression, the interactions between the microbiome and specific CRC driver mutations, especially those promoting metastasis, are not well defined.

In this study, we utilized triple mutant (Apc, Kras, Tp53; AKP) and quadruple mutant (Apc, Kras, Tp53, Smad4; AKPS) organoid-based orthotopic mouse models of CRC to investigate the impact of the SMAD4 mutation on microbiome composition.

Our results reveal significant differences in metastatic potential and microbial community dynamics between the two tumor models. AKPS tumors exhibited metastasis to the lymph nodes, liver, and lungs, while AKP tumors remained confined to the colon. Longitudinal microbiome analysis showed shifts in microbial composition within each tumor model. Both AKP and AKPS models demonstrated enrichment of Faecalibaculum and a decrease in Dubosiella over time; however, additional shifts were noted with distinct taxa associated with late-stage tumors in each group. Notably, the AKPS model exhibited higher relative abundances of pro-inflammatory taxa, including Turicibacter, Romboutsia, and Akkermansia, suggesting that the SMAD4 mutation promotes a more immunosuppressive and pro-metastatic microbiome profile.

These findings emphasize  the significance of SMAD4 mutation and microbiome modulation, revealing the interaction between host genetics and gut microbiota in driving colorectal cancer aggressiveness and suggesting potential microbial targets.