Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Front Immunol. 2022 Aug 4;13:951137. doi: 10.3389/fimmu.2022.951137. eCollection 2022.
Currently available prognostic tools and focused therapeutic methods result in unsatisfactory treatment of gastric cancer (GC). A deeper understanding of human epidermal growth factor receptor 2 (HER2)-coexpressed metabolic pathways may offer novel insights into tumour-intrinsic precision medicine.
The integrated multi-omics strategies (including transcriptomics, proteomics and metabolomics) were applied to develop a novel metabolic classifier for gastric cancer. We integrated TCGA-STAD cohort (375 GC samples and 56753 genes) and TCPA-STAD cohort (392 GC samples and 218 proteins), and rated them as transcriptomics and proteomics data, resepectively. 224 matched blood samples of GC patients and healthy individuals were collected to carry out untargeted metabolomics analysis.
In this study, pan-cancer analysis highlighted the crucial role of ERBB2 in the immune microenvironment and metabolic remodelling. In addition, the metabolic landscape of GC indicated that alanine, aspartate and glutamate (AAG) metabolism was significantly associated with the prevalence and progression of GC. Weighted metabolite correlation network analysis revealed that glycolysis/gluconeogenesis (GG) and AAG metabolism served as HER2-coexpressed metabolic pathways. Consensus clustering was used to stratify patients with GC into four subtypes with different metabolic characteristics (i.e. quiescent, GG, AAG and mixed subtypes). The GG subtype was characterised by a lower level of ERBB2 expression, a higher proportion of the inflammatory phenotype and the worst prognosis. However, contradictory features were found in the mixed subtype with the best prognosis. The GG and mixed subtypes were found to be highly sensitive to chemotherapy, whereas the quiescent and AAG subtypes were more likely to benefit from immunotherapy.
Transcriptomic and proteomic analyses highlighted the close association of HER-2 level with the immune status and metabolic features of patients with GC. Metabolomics analysis highlighted the co-expressed relationship between alanine, aspartate and glutamate and glycolysis/gluconeogenesis metabolisms and HER2 level in GC. The novel integrated multi-omics strategy used in this study may facilitate the development of a more tailored approach to GC therapy.
目前可用的预后工具和针对性治疗方法导致胃癌（GC）的治疗效果不尽人意。更深入地了解人表皮生长因子受体 2（HER2）共表达的代谢途径可能为肿瘤内在的精准医学提供新的见解。
采用整合的多组学策略（包括转录组学、蛋白质组学和代谢组学）开发用于胃癌的新型代谢分类器。我们整合了 TCGA-STAD 队列（375 个 GC 样本和 56753 个基因）和 TCPA-STAD 队列（392 个 GC 样本和 218 个蛋白质），并分别将其评为转录组学和蛋白质组学数据。收集了 224 对 GC 患者和健康个体的配对血液样本进行非靶向代谢组学分析。
本研究的泛癌分析强调了 ERBB2 在免疫微环境和代谢重编程中的关键作用。此外，GC 的代谢景观表明，丙氨酸、天冬氨酸和谷氨酸（AAG）代谢与 GC 的患病率和进展显著相关。加权代谢物相关网络分析显示，糖酵解/糖异生（GG）和 AAG 代谢是 HER2 共表达的代谢途径。共识聚类用于将 GC 患者分为具有不同代谢特征的四种亚型（即静止、GG、AAG 和混合亚型）。GG 亚型的 ERBB2 表达水平较低，炎症表型比例较高，预后最差。然而，在预后最佳的混合亚型中发现了相反的特征。GG 和混合亚型对化疗高度敏感，而静止和 AAG 亚型更可能受益于免疫治疗。
转录组学和蛋白质组学分析强调了 HER-2 水平与 GC 患者的免疫状态和代谢特征密切相关。代谢组学分析强调了 GC 中丙氨酸、天冬氨酸和谷氨酸与糖酵解/糖异生代谢以及 HER2 水平的共表达关系。本研究中使用的新型综合多组学策略可能有助于开发更适合 GC 治疗的方法。
