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Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite (Targeted metabolomics - fluoronucleotides)

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, 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.

Targeted metabolomics - fluoronucleotides is reported in the current study MTBLS9991.

Targeted metabolomics - 2methylisocitrate is reported in MTBLS9994.

INSTRUMENT(S): Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS9991 | MetaboLights | 2025-09-16

REPOSITORIES: MetaboLights

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			Action	DRS
	20190604_Ecoli_QC1.raw	Raw
	20190604_Ecoli_QC2.raw	Raw
	20190604_Ecoli_QC3.raw	Raw
	20190604_Ecoli_QC4.raw	Raw
	20190604_Ecoli_QC5.raw	Raw

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Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite (Targeted metabolomics - 2methylisocitrate)

Project description: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, 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. Targeted metabolomics - 2methylisocitrate is reported in the current study MTBLS9994.Targeted metabolomics - fluoronucleotides is reported in MTBLS9991.

2025-09-16 | MTBLS9994 | MetaboLights

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Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite

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