Martinez-Martinez, D., Peres, T.V., Gehling, K., Quintaneiro, L., Cabrera, C., Cherevatenko, M., Cutty, S.J., Best, L., Marinos, G., Zimmerman, J., Safoor, A., Chrysostomou, D., Mokochinski, J.B., Montoya, A., Brodesser, S., Zatorska, M., Scott, T., Andrew, I., Kramer, H., Begum, M., Zhang, B., Golding, B.T., Marchesi, J.R., Hirabayashi, S., Kaleta, C., Barr, A.R., Frezza, C., Cochemé, H.M., Cabreiro, F. (2025). Chemotherapy modulation by a cancer-associated microbiota metabolite.  Cell Syst. 16(9): 101397.

FBrf0263445

Research paper

Understanding how the microbiota produces regulatory metabolites is of significance for cancer and cancer therapy. Using a host-microbe-drug-nutrient 4-way screening approach, we evaluated the role of nutrition at the molecular level in the context of 5-fluorouracil toxicity. Notably, our screens identified the metabolite 2-methylisocitrate, which was found to be produced and enriched in human tumor-associated microbiota. 2-methylisocitrate exhibits anti-proliferative properties across genetically and tissue-diverse cancer cell lines, three-dimensional (3D) spheroids, and an in vivo Drosophila gut tumor model, where it reduced tumor dissemination and increased survival. Chemical landscape interaction screens identified drug-metabolite signatures and highlighted the synergy between 5-fluorouracil and 2-methylisocitrate. Multi-omic analyses revealed that 2-methylisocitrate acts via multiple cellular pathways linking metabolism and DNA damage to regulate chemotherapy. Finally, we converted 2-methylisocitrate into its trimethyl ester, thereby enhancing its potency. This work highlights the great impact of microbiome-derived metabolites on tumor proliferation and their potential as promising co-adjuvants for cancer treatment.