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Lookup NU author(s): Emeritus Professor Bernard Golding
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The AuthorsUnderstanding 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.
Author(s): Martinez-Martinez D, Peres TV, Gehling K, Quintaneiro L, Cabrera C, Cherevatenko M, Cutty SJ, Best L, Marinos G, Zimmerman J, Safoor A, Chrysostomou D, Mokochinski JB, Montoya A, Brodesser S, Zatorska M, Scott T, Andrew I, Kramer H, Begum M, Zhang B, Golding BT, Marchesi JR, Hirabayashi S, Kaleta C, Barr AR, Frezza C, Cocheme HM, Cabreiro F
Publication type: Article
Publication status: Published
Journal: Cell Systems
Year: 2025
Volume: 16
Issue: 9
Print publication date: 17/09/2025
Online publication date: 10/09/2025
Acceptance date: 18/08/2025
Date deposited: 02/10/2025
ISSN (print): 2405-4712
ISSN (electronic): 2405-4720
Publisher: Cell Press
URL: https://doi.org/10.1016/j.cels.2025.101397
DOI: 10.1016/j.cels.2025.101397
Data Access Statement: Metabolomics, proteomics, and RNA-seq data have been deposited at GEO, PRIDE, and MetaboLights and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. This paper analyzes existing, publicly available data. These accession numbers for the datasets are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Original code has been deposited at GitHub (https://github.com/Cabreiro-Lab/micit_cancer_code/) and is publicly available as of the date of publication. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. DOIs are listed in the key resources table.
PubMed id: 40934913
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