The glutamine-aspartate metabolic tradeoff between fast growth and metabolic flexibility.

Cancer cells develop unique addictions to nutrients, offering attractive opportunities for clinical intervention. However, how cancer cells orchestrate and benefit from metabolic rewiring remain fundamental open questions. Here, we developed a systematic framework to investigate nutrient dependencies and applied it to study glutamine addiction. By measuring metabolite exchange rates across 54 cancer cell lines with different levels of dependency on extracellular glutamine and in human stem cells, we discovered that a dualistic regulation of glutamate biosynthesis from glutamine or aspartate, driven by the tissue of origin, generates a tradeoff between fast growth and metabolic flexibility. Monitoring dynamic metabolic adaptation to glutamine deprivation showed that the role of glutamine as limiting substrate in purine biosynthesis is not responsible for glutamine dependency. Rather, growth arrest is mediated by glutamine as a signaling molecule. Our approach opens new opportunities to map, mechanistically investigate and pharmacologically interfere with metabolic dependencies, beyond glutamine addiction.