Introduction
Although glutamine is a nonessential amino acid in normal cells, glutamine demand is dramatically increased in cancer, supporting a range of metabolic processes including mitochondrial ATP production, protein synthesis, purine and pyrimidine biosynthesis. We previously showed that triple-negative breast cancer (TNBC) cells dramatically increase their glutamine uptake to sustain their unique glutamine metabolism, thereby supporting in vitro growth and in vivo tumour formation1.
Results
In this study, we undertook extensive metabolomic analyses of Luminal A (glutamine-independent) and triple-negative breast cancer (TNBC; glutamine-dependent) breast cancer subtypes. Our data show that TNBC cells have a unique metabolic profile, where they rely on a non-canonical use of glutamine in the TCA cycle2. Glutamine carbon is only routed once through the TCA cycle, before exiting and being converted to glutamate and exported from the cells in exchange for cystine. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes of glucose, thereby replenishing TCA cycle intermediates. The coupling of glucose and glutamine catabolism appears hard-wired via a distinct TNBC gene expression profile, which is significantly upregulated in TCGA, METABRIC and TCCLE breast cancer datasets. This unique metabolic pathway strips and then sequester glutamine nitrogen, but hampers the ability of TNBC cells to oxidise glucose when glutamine is limiting, providing a novel therapeutic vulnerability.
However, our ability to study these novel metabolic pathways and therapeutic vulnerabilities are hampered by the use of traditional culture conditions that do not reflect in vivo metabolite or gas levels. As such, we have also utilised a novel physiological culture method which allows us for the first time to culture cell lines and explants under similar conditions to what they would experience in the body, which can be used to better study drug responses in the lab.
Conclusions
These data suggest provide a new understanding of how metabolically rigid TNBC cells are sensitive to glutamine deprivation and a way to select vulnerable TNBC subtypes that may be responsive to metabolic-targeted therapies. In addition, by better modelling the in vivo tumour nutrient environment, we can now more accurately determine drug responses which may facilitate more effective translation of drugs into the clinic.