Chemotherapy modulation by a cancer-associated microbiota metabolite
| Title: | Chemotherapy modulation by a cancer-associated microbiota metabolite |
|---|---|
| Authors: | 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 |
| Source: | Cell Systems, 17 September 2025 |
| Publisher Information: | Cell Press |
| Publication Year: | 2025 |
| Collection: | Newcastle University Library ePrints Service |
| Description: | © 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. |
| Document Type: | article in journal/newspaper |
| File Description: | application/pdf |
| Language: | unknown |
| Relation: | https://eprints.ncl.ac.uk/307893; https://eprints.ncl.ac.uk/fulltext.aspx?url=307893/621A11C7-6785-4542-96A7-D32C62E58BDC.pdf&pub_id=307893 |
| Availability: | https://eprints.ncl.ac.uk/307893 |
| Rights: | https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: | edsbas.4929BE32 |
| Database: | BASE |