Cells must adapt to fluctuations in nutrient availability to thrive. Among these nutrients, glutamine--a vital amino acid--plays a significant role in cellular metabolism. It is crucial for synthesizing proteins and DNA, and without it, cells struggle to grow and proliferate.
Cancer cells exemplify this phenomenon, often described as exhibiting "glutamine addiction," where they become heavily reliant on this nutrient. While this dependency presents a potential vulnerability, many cancers have developed strategies to circumvent it. Recent research published in the journal Molecular Cell, led by Alexis Jourdain, an assistant professor in the Department of Immunobiology at the University of Lausanne's Faculty of Biology and Medicine, uncovers the cellular mechanisms that facilitate this adaptability.
The Role of Pyruvate and Vitamin B7 in Cell Proliferation
The investigation, spearheaded by Dr. Miriam Lisci, a postdoctoral researcher in Jourdain's lab, concentrated on carbon-rich molecules, particularly pyruvate. These molecules enable cells to continue dividing even in conditions of glutamine scarcity.
The research identified a mitochondrial enzyme known as pyruvate carboxylase as essential for this process. This enzyme is dependent on vitamin B7 (biotin) for its activity. In scenarios where vitamin B7 is lacking, the enzyme ceases to function, halting cell growth. Consequently, biotin serves as a "metabolic license," facilitating pyruvate's entry into the cell's energy framework and compensating for glutamine deficiency.
Impact of FBXW7 Gene Mutations on Cancer Dependency
The study also revealed a novel function of the FBXW7 gene, often associated with cancer. "When FBXW7 is mutated--common in various cancers--pyruvate carboxylase is partially lost, leading to inefficient pyruvate utilization and increased reliance on glutamine," explains Lisci, the lead author.
The researchers demonstrated that specific mutations in the FBXW7 gene found in patients can directly enhance this glutamine dependence. These insights were achieved through collaborations with the metabolomics and proteomics platforms at the Faculty of Biology and Medicine and with Prof. Owen Skinner's team at Northeastern University in the United States.
Understanding Treatment Challenges and Future Directions
The findings provide clarity on why certain therapies targeting glutamine may not always be effective, as cancer cells can shift to alternative metabolic routes to survive.
"In the long term, this research paves the way for a deeper understanding of the metabolic vulnerabilities in cancers and for the development of innovative treatment strategies that consider the metabolic flexibility of tumor cells, particularly by targeting multiple pathways at once," concludes Jourdain, the senior author of the study.
