Graduate school of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea.
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Korea.
Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2217826120. doi: 10.1073/pnas.2217826120. Epub 2023 May 16.
Molecular classification of gastric cancer (GC) identified a subgroup of patients showing chemoresistance and poor prognosis, termed SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type in this study. Here, we show that SEM-type GC exhibits a distinct metabolic profile characterized by high glutaminase (GLS) levels. Unexpectedly, SEM-type GC cells are resistant to glutaminolysis inhibition. We show that under glutamine starvation, SEM-type GC cells up-regulate the 3 phosphoglycerate dehydrogenase (PHGDH)-mediated mitochondrial folate cycle pathway to produce NADPH as a reactive oxygen species scavenger for survival. This metabolic plasticity is associated with globally open chromatin structure in SEM-type GC cells, with ATF4/CEBPB identified as transcriptional drivers of the PHGDH-driven salvage pathway. Single-nucleus transcriptome analysis of patient-derived SEM-type GC organoids revealed intratumoral heterogeneity, with stemness-high subpopulations displaying high GLS expression, a resistance to GLS inhibition, and ATF4/CEBPB activation. Notably, coinhibition of GLS and PHGDH successfully eliminated stemness-high cancer cells. Together, these results provide insight into the metabolic plasticity of aggressive GC cells and suggest a treatment strategy for chemoresistant GC patients.
本研究中，胃癌（GC）的分子分类确定了一组表现出化疗耐药和预后不良的患者亚群，称为 SEM（Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal）型。在这里，我们表明 SEM 型 GC 表现出独特的代谢特征，其特征是谷氨酰胺酶（GLS）水平较高。出乎意料的是，SEM 型 GC 细胞对谷氨酰胺分解抑制具有抗性。我们表明，在谷氨酰胺饥饿下，SEM 型 GC 细胞上调 3-磷酸甘油酸脱氢酶（PHGDH）介导的线粒体叶酸循环途径，以产生 NADPH 作为活性氧清除剂以维持生存。这种代谢可塑性与 SEM 型 GC 细胞中整体开放的染色质结构有关，ATF4/CEBPB 被确定为 PHGDH 驱动的补救途径的转录驱动因子。来自患者来源的 SEM 型 GC 类器官的单细胞转录组分析显示出肿瘤内异质性，其中干性高亚群表现出高 GLS 表达、对 GLS 抑制的抗性以及 ATF4/CEBPB 的激活。值得注意的是，GLS 和 PHGDH 的联合抑制成功消除了干性高的癌细胞。总之，这些结果深入了解了侵袭性 GC 细胞的代谢可塑性，并为化疗耐药的 GC 患者提供了一种治疗策略。
