Metformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers

Area of Science:

• Oncology
• Metabolomics
• Mitochondrial Biology

Background:

• Metformin is a widely used diabetes drug with potential anticancer properties.
• Its mechanism in cancer, particularly patient response predictors, is not fully understood.
• Systemic effects on glucose metabolism are known, but cancer-specific molecular determinants are elusive.

Purpose of the Study:

• To investigate the molecular effects of metformin in ovarian cancer using an integrative metabolomics approach.
• To identify metabolic signatures associated with metformin response in cancer patients.
• To elucidate the mechanistic basis of metformin's action in cancer mitochondria.

Main Methods:

• Integrative metabolomics analysis of metformin-treated ovarian cancer patient biopsies.
• Stable isotope tracing to track nutrient utilization in mitochondria.
• Comparison of metabolic profiles between patient tumors and animal models.

Main Results:

• Metformin was detected in patient tumor biopsies.
• Key affected pathways included nucleotide metabolism, redox balance, and energy status, all linked to mitochondrial function.
• A distinct metabolic signature in a patient with exceptional outcome matched that of a responsive animal tumor.
• Mechanistic studies revealed impaired mitochondrial nutrient utilization adaptation.

Conclusions:

• Metformin impacts mitochondrial metabolism in ovarian cancer.
• A specific metabolic signature may predict patient response to metformin therapy.
• Defective mitochondrial nutrient adaptation is a potential mechanism underlying metformin's anticancer effects.
• Findings offer insights for precision medicine approaches in cancer treatment with metformin.