Chemotherapy modulation by a cancer-associated microbiota metabolite
Year: 2025
Type: article
Abstract: 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.
Source: Cell Systems
Authors: Daniel Martinez-Martinez, Tanara V. Peres, Kristin Gehling, Leonor Quintaneiro, Cecilia Cabrera, Maksym Cherevatenko, Stephen J. Cutty, Lena Best, Georgios Marinos, Johannes Zimmerman, Ayesha Safoor, Despoina Chrysostomou, Joao B. Mokochinski, Alex Montoya, Susanne Brodesser, Michalina Zatorska, Timothy Scott, Ivan Andrew, Holger Kramer, Masuma Begum, Bian Zhang, Bernard T. Golding, Julian R. Marchesi, Susumu Hirabayashi, Christoph Kaleta, Alexis R. Barr, Christian Frezza, Helena M. Cochemé, Filipe Cabreiro
Institutions: Hammersmith Hospital, MRC London Institute of Medical Sciences, Imperial College London, Medical Research Council, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne, Christian-Albrechts-Universität zu Kiel, Newcastle University
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $9,350
Funders: Wellcome Trust, Leverhulme Trust, Royal Society, Imperial College London, Imperial College Healthcare NHS Trust, Deutsche Forschungsgemeinschaft, School of Medicine, Johns Hopkins University, Medical Research Council, Center for Molecular Medicine Cologne, University of Cologne, NIHR Imperial Biomedical Research Centre, Office of Research Infrastructure Programs, National Institutes of Health
OpenAlex ID: W4414111748