A research group at the University of Lausanne (Unil) has identified a new mechanism that exposes the vulnerability of tumor cells when they are deprived of vitamin B7.
The ability of cells to adapt to fluctuations in nutrient availability is essential to life. Yet, some cells become highly dependent on glutamine, an amino acid that plays a central role in cellular metabolism. This nutrient provides the essential building blocks for protein and DNA synthesis, and cells stop proliferating without it.
This is the case for cancer cells: "glutamine addiction" is a well-known vulnerability of tumors, but many cancers manage to bypass it. In a study published in the journal Molecular Cell, the team led by Alexis Jourdain, assistant professor in the Department of Immunobiology (DIB) at Unil's Faculty of Biology and Medicine (FBM), advances the understanding of cellular mechanisms that until now were poorly understood.
Cells, show your papers!
The work led by Dr. Miriam Lisci, a postdoctoral researcher in Prof. Jourdain's laboratory , highlighted carbon-rich molecules —particularly pyruvate — that allow cells to continue dividing even in the absence of glutamine. The experiments reveal that this effect requires a mitochondrial enzyme called pyruvate carboxylase, which itself needs vitamin B7 (or biotin) to function. Without this vitamin, the enzyme is inactive and cells remain stalled. Biotin thus acts as a true "metabolic license," enabling pyruvate to fuel the cells' energy cycle and compensate for the lack of glutamine.
The key role of the FBXW7 gene
The researchers also discovered a previously unknown role for FBXW7, a gene known for its involvement in many cancers. "When FBXW7 is mutated — a situation that is frequent in certain cancers — pyruvate carboxylase partially disappears, pyruvate can no longer be used efficiently, and cells become dependent on glutamine," explains Miriam Lisci, first author of the article. The scientists even showed that certain FBXW7 mutations found in patients directly induce this metabolic addiction. The results were obtained thanks to collaborations with the FBM's metabolomics and proteomics platforms, as well as with the team of Prof. Owen Skinner at Northeastern University in the United States.
This publication also highlights why some therapies targeting glutamine fail: cancer cells can activate alternative metabolic pathways. "In the longer term, this research opens up new avenues for better understanding the metabolic vulnerabilities of cancers and for designing innovative therapeutic strategies that take into account the great metabolic flexibility of tumor cells, notably by targeting several metabolic pathways simultaneously," concludes Alexis Jourdain, senior author of the study.
