谷氨酰胺代谢重编程的癌种特异性探究

谷氨酰胺代谢是肿瘤的重要代谢特征，已成为新的抗癌靶点。尽管体外培养的肿瘤细胞广泛依赖谷氨酰胺代谢，但近期有研究指出体内肺癌并不依赖谷氨酰胺，引发谷氨酰胺代谢在体内肿瘤中是否发挥作用的争议。我们前期分析了不同肿瘤类型中谷氨酰胺代谢关键限速酶-谷氨酰胺酶（Glutaminase，GLS）的表达，发现GLS在结肠癌、肝癌等肿瘤组织中表达上调，而在肺癌、肾癌等肿瘤组织中表达下调。利用小鼠肿瘤模型，采用U-13C标记谷氨酰胺示踪代谢流发现，结肠癌组织相较癌旁更快代谢谷氨酰胺回补三羧酸循环，而肺癌组织基本不依赖谷氨酰胺。GLS抑制剂CB-839可有效抑制小鼠结肠肿瘤生长，而肺肿瘤不受影响。本课题计划利用生物信息学、小鼠肿瘤模型和同位素示踪代谢流技术，探究不同癌种中谷氨酰胺代谢重编程的特征及CB-839治疗效果。通过验证谷氨酰胺代谢重编程具有癌种特异性的假设，为靶向谷氨酰胺代谢的抗肿瘤临床应用提供依据。

The reprogramming of glutamine metabolism is a hallmark of cancer metabolism. Targeting glutamine metabolism has been developed as a novel cancer therapeutic strategy. A recent study showed that the growth of lung tumor did not rely on glutamine metabolism in vivo, although lung cancer cells rely on glutamine in vitro. It results in a controversy about whether glutamine metabolism plays an important role in tumorigenesis in vivo. We analyzed the expression of glutamine metabolism-related genes in different tumor types. Glutaminase (GLS), the rate-limiting enzyme in glutamine metabolism pathway, was upregulated in colorectal cancer, liver cancer etc., while downregulated in lung cancer, kidney cancer etc. Consistently, in mouse model, glutamine was rapidly metabolized and provided carbon source for TCA cycle in cancerous tissues compared with normal tissues in colorectal cancer. However, glutamine entered TCA cycle with similar rate in cancerous tissues compared with normal tissues in lung cancer. CB-839 (GLS inhibitor) could inhibit growth of colorectal tumor but have little effect on lung tumors in vivo. Based on those findings, we propose a hypothesis that glutamine metabolic reprogramming has tumor-type specificity. We will further use bio-informatics, mouse tumor models and metabolic flux tracing techniques to identify the differences of glutamine flux in different types of tumor, the correlation between glutamine metabolism-related gene expression and glutamine flux, and the types of cancer most suitable for glutamine metabolism targeting therapy. In this project, we will verify our hypothesis that glutamine metabolism reprogramming plays diverse role in different cancer type, and provide evidences for clinical application of targeting glutamine metabolism.