Glutamine metabolic microenvironment drives M2 macrophage polarization tomediate trastuzumab resistance in HER2-positive gastric cancer
作者机构：Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP.R.China School of Biomedical EngineeringSouthern Medical UniversityGuangzhouGuangdongP.R.China School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouGuangdongP.R.China Department of Medical OncologySun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP.R.China
出 版 物：《Cancer Communications》 (癌症通讯（英文）)
年 卷 期：2023年第43卷第8期
页 面：909-937页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：National Natural Science Foundation of China Grant/Award Number:82073325
主 题：Gastric cancer glutamine metabolism macrophage mathematical model microvesicles trastuzumab
摘 要：Background:Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2(HER2)-positive gastric ***,the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit,and there is currently no effective reversal *** 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 *** study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these ***:Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome *** were used to analyze cell subtypes,metabolic pathways,and molecular signaling *** in microenvironmental indicators(such as macrophage,angiogenesis,and metabolism)were verified by immunofluorescence(IF)and immunohistochemical(IHC)***,a multi-scale agent-based model(ABM)was *** effects of combination treatment were further validated in nude mice to verify these effects predicted by the ***:Based on transcriptome sequencing,molecular biology,and in vivo experiments,we found that the level of glutamine metabolism in trastuzumabresistant HER2-positive cells was increased,and glutaminase 1(GLS1)was significantly ***,tumor-derived GLS1 microvesicles drove M2macrophage ***,angiogenesis promoted trastuzumab *** showed high glutamine metabolism,M2 macrophage polarization,and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and ***,the cell division cycle 42(CDC42)promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B(NF-κB)p65 and drove GLS1microvesicle secretion through IQmotif-containing GTPase-activating protein 1(IQGAP1).Based on the ABM and
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