Universität zu Köln

Martinez-Martinez, Daniel, Peres, Tanara V., Gehling, Kristin ORCID: 0000-0002-7933-3777, Quintaneiro, Leonor, Cabrera, Cecilia, Cherevatenko, Maksym ORCID: 0009-0003-0938-1233, Cutty, Stephen J., Best, Lena, Marinos, Georgios, Zimmerman, Johannes, Safoor, Ayesha, Chrysostomou, Despoina, Mokochinski, Joao B., Montoya, Alex, Brodesser, Susanne ORCID: 0000-0001-5631-0663, Zatorska, Michalina, Scott, Timothy, Andrew, Ivan, Kramer, Holger, Begum, Masuma, Zhang, Bian, Golding, Bernard T., Marchesi, Julian R., Hirabayashi, Susumu, Kaleta, Christoph, Barr, Alexis R., Frezza, Christian, Cochemé, Helena M. and Cabreiro, Filipe ORCID: 0000-0002-3696-4843 (2025). Chemotherapy modulation by a cancer-associated microbiota metabolite. Cell Systems, 16 (9). pp. 1-45. Elsevier. ISSN 2405-4712

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Abstract

[Artikel-Nr.: 101397] 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Martinez-Martinez, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Peres, Tanara V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehling, Kristin UNSPECIFIED https://orcid.org/0000-0002-7933-3777 UNSPECIFIED Quintaneiro, Leonor UNSPECIFIED UNSPECIFIED UNSPECIFIED Cabrera, Cecilia UNSPECIFIED UNSPECIFIED UNSPECIFIED Cherevatenko, Maksym UNSPECIFIED https://orcid.org/0009-0003-0938-1233 UNSPECIFIED Cutty, Stephen J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Best, Lena UNSPECIFIED UNSPECIFIED UNSPECIFIED Marinos, Georgios UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmerman, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Safoor, Ayesha UNSPECIFIED UNSPECIFIED UNSPECIFIED Chrysostomou, Despoina UNSPECIFIED UNSPECIFIED UNSPECIFIED Mokochinski, Joao B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Montoya, Alex UNSPECIFIED UNSPECIFIED UNSPECIFIED Brodesser, Susanne UNSPECIFIED https://orcid.org/0000-0001-5631-0663 UNSPECIFIED Zatorska, Michalina UNSPECIFIED UNSPECIFIED UNSPECIFIED Scott, Timothy UNSPECIFIED UNSPECIFIED UNSPECIFIED Andrew, Ivan UNSPECIFIED UNSPECIFIED UNSPECIFIED Kramer, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Begum, Masuma UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Bian UNSPECIFIED UNSPECIFIED UNSPECIFIED Golding, Bernard T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marchesi, Julian R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hirabayashi, Susumu UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaleta, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Barr, Alexis R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frezza, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Cochemé, Helena M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cabreiro, Filipe UNSPECIFIED https://orcid.org/0000-0002-3696-4843 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-809765
Identification Number:	10.1016/j.cels.2025.101397
Journal or Publication Title:	Cell Systems
Volume:	16
Number:	9
Page Range:	pp. 1-45
Number of Pages:	45
Date:	17 September 2025
Publisher:	Elsevier
ISSN:	2405-4712
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language cancer-associated microbiota ; cancer metabolism ; chemotherapy ; microbial metabolism ; methylcitrate cycle host-microbe interactions English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80976