School of Mathematics and Statistics, The University of Sydney, Camperdown, NSW, Australia.
Origins of Cancer Program, Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.
Oncogene. 2022 Aug;41(34):4066-4078. doi: 10.1038/s41388-022-02408-5. Epub 2022 Jul 18.
Glutamine is a conditionally essential nutrient for many cancer cells, but it remains unclear how consuming glutamine in excess of growth requirements confers greater fitness to glutamine-addicted cancers. By contrasting two breast cancer subtypes with distinct glutamine dependencies, we show that glutamine-indispensable triple-negative breast cancer (TNBC) cells rely on a non-canonical glutamine-to-glutamate overflow, with glutamine carbon routed once through the TCA cycle. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes and replenishes TCA cycle intermediates in TNBC cells, a process that achieves net oxidation of glucose but not glutamine. The coupling of glucose and glutamine catabolism appears hard-wired via a distinct TNBC gene expression profile biased to strip and then sequester glutamine nitrogen, but hampers the ability of TNBC cells to oxidise glucose when glutamine is limiting. Our results 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.
谷氨酰胺是许多癌细胞的条件必需营养素，但目前尚不清楚过量摄入谷氨酰胺如何使依赖谷氨酰胺的癌症更具适应性。通过对比两种具有不同谷氨酰胺依赖性的乳腺癌亚型，我们表明，谷氨酰胺不可或缺的三阴性乳腺癌（TNBC）细胞依赖于非经典的谷氨酰胺到谷氨酸的溢出途径，其中谷氨酰胺碳仅穿过 TCA 循环一次。重要的是，这种单通道谷氨酰胺分解增加了 TCA 循环通量并补充了 TNBC 细胞中的 TCA 循环中间产物，这一过程实现了葡萄糖的净氧化，但不是谷氨酰胺。通过偏向于剥夺和隔离谷氨酰胺氮的独特的 TNBC 基因表达谱，葡萄糖和谷氨酰胺分解代谢的偶联似乎是硬连线的，但当谷氨酰胺有限时，会阻碍 TNBC 细胞氧化葡萄糖的能力。我们的研究结果提供了对代谢刚性 TNBC 细胞如何对谷氨酰胺剥夺敏感的新认识，并为选择可能对代谢靶向治疗有反应的脆弱 TNBC 亚型提供了一种方法。
