Glutamine metabolic microenvironment drives M2 macrophage polarization to mediate trastuzumab resistance in HER2‐positive gastric cancer

作者：Xingbin Hu, Zhenfeng Ma, Beibei Xu, Shulong Li, Zhiqi Yao, Bishan Liang, Jiao Wang, Wangjun Liao, Lin Li, Chunling Wang, Siting Zheng, Qijing Wu, Qiong Huang, Le Yu, Feng‐Hua Wang, Min Shi · 发表于：癌症：英文版 · 年份：2023 · DOI：10.1002/cac2.12459 · 被引用次数：109 · 研究领域：HER2/EGFR in Cancer Research、Immune cells in cancer、Cancer Cells and Metastasis

BACKGROUND: Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2 (HER2)-positive gastric cancer. However, the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit, and there is currently no effective reversal measure. Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves, while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking. This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients. METHODS: Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing. Bioinformatics were used to analyze cell subtypes, metabolic pathways, and molecular signaling pathways. Changes in microenvironmental indicators (such as macrophage, angiogenesis, and metabolism) were verified by immunofluorescence (IF) and immunohistochemical (IHC) analyses. Finally, a multi-scale agent-based model (ABM) was constructed. The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM. RESULTS: Based on transcriptome sequencing, molecular biology, and in vivo experiments, we found that the level of glutamine metabolism in trastuzumab-resistant HER2-positive cells was increased, and glutaminase 1 (GLS1) was significantly overexpressed. Meanwhile, tu...