Chemotherapy modulation by a cancer-associated microbiota metabolite

Area of Science:

• Microbiology
• Metabolomics
• Cancer Biology
• Pharmacology

Background:

• Microbiota-derived metabolites play a crucial role in cancer development and treatment.
• Understanding the molecular mechanisms of host-microbe interactions is vital for advancing cancer therapy.

Purpose of the Study:

• To investigate the role of nutrition and microbial metabolites in the context of 5-fluorouracil (5-FU) chemotherapy.
• To identify and characterize novel microbial metabolites with anti-cancer properties.

Main Methods:

• A 4-way screening approach (host-microbe-drug-nutrient) was employed.
• In vitro assays using cancer cell lines and 3D spheroids, and in vivo studies using a Drosophila gut tumor model.
• Chemical landscape interaction screens and multi-omic analyses were performed.

Main Results:

• The metabolite 2-methylisocitrate was identified as being produced by tumor-associated microbiota.
• 2-methylisocitrate demonstrated anti-proliferative effects across diverse cancer models and improved survival in vivo.
• Synergy was observed between 2-methylisocitrate and 5-fluorouracil, with the metabolite modulating chemotherapy response through metabolic and DNA damage pathways.
• A trimethyl ester derivative of 2-methylisocitrate showed enhanced potency.

Conclusions:

• Microbiome-derived 2-methylisocitrate possesses significant anti-tumor properties.
• 2-methylisocitrate acts as a regulator of chemotherapy, linking metabolism and DNA damage.
• This metabolite holds promise as a co-adjuvant for enhancing cancer treatment efficacy.