Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite
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ABSTRACT:
PROVIDER: PRJNA1098747 | ENA |
REPOSITORIES: ENA
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Project description:The microbiota plays a major role in cancer. How the microbiota interacts with nutrients to produce regulatory metabolites is of significance for 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, we identified the metabolite 2-methylisocitrate to be produced and enriched in human tumor-associated microbiomes. 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. Drug-metabolite screening traced the chemotherapeutic signatures indicating synergy between 5-fluorouracil and 2-methylisocitrate, and multi-omic analyses revealed that 2-methylisocitrate acts via multiple cellular pathways linking metabolism and DNA damage to regulate chemotherapy. Finally, building on nature’s template, we altered the chemical structure of 2-methylisocitrate, 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.
2025-09-15 | GSE263706 | GEO
Project description:<p>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.</p><p><br></p><p><strong>Targeted metabolomics - fluoronucleotides</strong> is reported in the current study <strong>MTBLS9991</strong>.</p><p><strong>Targeted metabolomics - 2methylisocitrate</strong> is reported in <strong>MTBLS9994</strong>.</p>
2025-09-16 | MTBLS9991 | MetaboLights
Project description:<p>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.</p><p><br></p><p><strong>Targeted metabolomics - 2methylisocitrate</strong> is reported in the current study <strong>MTBLS9994</strong>.</p><p><strong>Targeted metabolomics - fluoronucleotides</strong> is reported in <strong>MTBLS9991</strong>.</p>
2025-09-16 | MTBLS9994 | MetaboLights
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2024-12-09 | GSE246268 | GEO
Project description:We report the first case series of ICI associated colitis successfully treated with fecal microbiota transplantation (FMT), with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T cells (Tregs) within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
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Project description:Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers like melanoma, however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here we identify the gut microbiota as playing a previously unrecognized, critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances Tc1-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate in vitro and promote tumor antigen-specific Tc1 immunity in vivo. Mechanistically, we identified the transcription factor nuclear factor erythroid 2-related factor-2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement in vitro and a key player in the exercise-mediated antitumor effect in vivo. Finally, we identify human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity and support its functional role in driving melanoma suppression.
2025-07-23 | GSE294230 | GEO
Project description:A high-sugar diet induces lifestyle-associated metabolic diseases, such as obesity and diabetes, which may underlie the pro-tumor effects of a high-sugar diet. We supplied GL261 syngeneic glioblastoma (GBM) model mice with a short-term high-glucose diet (HGD) and found an increased survival rate with no evidence of metabolic disease. Modulation of the gut microbiota by an HGD was critical for enhancing the anti-tumor immune response. Single-cell RNA sequencing showed that modulation of the gut microbiota by an HGD increased the T cell-mediated anti-tumor immune response in GBM mice. We found that the cytotoxic CD4+ T cell population in GBM mice increased due to synergy with anti-PD-1 immune checkpoint inhibitors, but this depended on an HGD. Thus, we determined that an HGD enhanced anti-tumor immune responses in GBM mice through changes in the gut microbiota and suggest that the role of an HGD in GBM should be re-examined.
2023-09-19 | GSE222192 | GEO
Project description:Modulation of the tumor promoting functions of cancer associated fibroblasts by PDE5 inhibition increases the efficacy of chemotherapy in human preclinical models of edophageal adenocarcinoma
2022-08-12 | PXD031148 | Pride
Project description:Hepatocellular carcinoma is one of the most prevalent malignancies worldwide, and the role of stress in hepatocellular carcinoma progression remains incompletely understood. In this study, we integrated clinical and preclinical models to investigate how stress-associated gut microbiota remodeling contributes to hepatocellular carcinoma progression. Stress profoundly altered the gut microbiota, with Phocaeicola vulgatus significantly reduced. Restoration of Phocaeicola vulgatus or administration of its tryptophan-derived metabolite indole-3-propionic acid attenuated hepatocellular carcinoma progression in vivo. Single-cell RNA sequencing was performed to characterize changes in the hepatocellular carcinoma tumor microenvironment. Indole-3-propionic acid treatment reduced endothelial JAM2 expression and was associated with reduced JAM2-F11R-mediated endothelial-macrophage crosstalk. These findings support a role for the stress-gut microbiota-metabolite-tumor microenvironment axis in hepatocellular carcinoma progression and suggest potential translational targets for microbiome-based therapeutic strategies.
2026-05-13 | GSE330363 | GEO
Project description:Effect of Metabolite Treatment on Murine Faecal Microbiota
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