Cheng Xiangshu, Zhang Shuhao, Meng Xin, Chen Rui, Tang Hao, Wang Jiacheng, Jiang Yongshuai, Zhang Ruijie
College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Heilongiiang Province, China.
Sci Rep. 2025 Jul 1;15(1):20996. doi: 10.1038/s41598-025-05179-7.
Due to the high heterogeneity among breast cancer (BRCA) patients, most individuals show a limited response rate to one specific treatment. The metabolic plasticity of BRCA cells is one of the main causes of their heterogeneity, affecting not only their own growth and function but also their metabolites have an impact on the tumor immune microenvironment (TIME). However systematic evaluation of metabolic pathways in BRCA is lacking. We identified BRCA metabolic subtypes (BCMS) by consensus clustering 26 KEGG/Reactome pathways in the TCGA BRCA discovery cohort (n = 1094). Nine independent bulk transcriptome cohorts (total n > 4000), including METABRIC and GEO datasets, were used for validation via random forest classification. To characterize BCMS, we applied an analytical framework encompassing functional enrichment (GSEA), immune infiltration (Mcpcounter), clinical correlation, drug sensitivity (oncoPredict) on bulk transcriptome data, cell-cell communication analysis (CellChat) on single-cell RNA sequencing (scRNA-seq) data, and spatial co-localization analysis (CellTrek) on spatial RNA sequencing (spRNA-seq) data. We identified two distinct BCMS. BCMS-I exhibited upregulated lipid metabolism-related pathways, characterized by immune activation, a better prognosis, and higher infiltration of immune cells, including B cells, T cells, NK cells, macrophages, and neutrophils. Spatial co-localization analysis further revealed that BCMS-I demonstrated spatial co-localization with immune cells. In contrast, BCMS-II showed upregulation of amino acid and vitamin metabolism-related pathways, with tumor cell proliferation, a poorer prognosis, and a lack of immune cell infiltration. The immune activation in BCMS-I is marked by the significant activation of the MHC-I signaling pathway in interactions between tumor cells and T/NK cells, and of the MHC-II signaling pathway in interactions between tumor cells and dendritic cells/macrophages. In contrast, the proliferative characteristics of BCMS-II are associated with the co-activation of the GRN signaling pathway by myeloid immune cells and stromal cells within the tumor microenvironment. Drug sensitivity analysis revealed that BCMS-II was highly sensitive to Ganitumab, Carboplatin + ABT-888, and Pembrolizumab. This study established a novel Breast Cancer Metabolic Subtyping System (BCMSS) based on metabolic pathway analysis. Our findings highlight the heterogeneity of BRCA in terms of metabolic features, immune characteristics, clinical prognosis, and drug sensitivity. The novel classification system provides valuable insights for clinical diagnosis and treatment, serving as a foundation for precision diagnosis and personalized therapies in BRCA.
由于乳腺癌(BRCA)患者之间存在高度异质性,大多数个体对一种特定治疗的反应率有限。BRCA细胞的代谢可塑性是其异质性的主要原因之一,不仅影响其自身的生长和功能,而且其代谢产物还会对肿瘤免疫微环境(TIME)产生影响。然而,目前缺乏对BRCA中代谢途径的系统评估。我们通过对TCGA BRCA发现队列(n = 1094)中的26条KEGG/Reactome途径进行共识聚类,确定了BRCA代谢亚型(BCMS)。九个独立的批量转录组队列(总数n > 4000),包括METABRIC和GEO数据集,通过随机森林分类进行验证。为了表征BCMS,我们应用了一个分析框架,包括对批量转录组数据的功能富集(GSEA)、免疫浸润(Mcpcounter)、临床相关性、药物敏感性(oncoPredict),对单细胞RNA测序(scRNA-seq)数据的细胞间通讯分析(CellChat),以及对空间RNA测序(spRNA-seq)数据的空间共定位分析(CellTrek)。我们确定了两种不同的BCMS。BCMS-I表现出脂质代谢相关途径上调,其特征为免疫激活、预后较好以及免疫细胞(包括B细胞、T细胞、NK细胞、巨噬细胞和中性粒细胞)浸润较高。空间共定位分析进一步显示,BCMS-I与免疫细胞表现出空间共定位。相比之下,BCMS-II显示氨基酸和维生素代谢相关途径上调,伴有肿瘤细胞增殖、预后较差且缺乏免疫细胞浸润。BCMS-I中的免疫激活以肿瘤细胞与T/NK细胞相互作用中MHC-I信号通路的显著激活,以及肿瘤细胞与树突状细胞/巨噬细胞相互作用中MHC-II信号通路的显著激活为特征。相比之下,BCMS-II的增殖特征与肿瘤微环境中髓样免疫细胞和基质细胞对GRN信号通路的共同激活有关。药物敏感性分析显示,BCMS-II对甘尼单抗、卡铂 + ABT-888和派姆单抗高度敏感。本研究基于代谢途径分析建立了一种新型的乳腺癌代谢分型系统(BCMSS)。我们的研究结果突出了BRCA在代谢特征、免疫特性、临床预后和药物敏感性方面的异质性。这种新型分类系统为临床诊断和治疗提供了有价值的见解,为BRCA的精准诊断和个性化治疗奠定了基础。
Cochrane Database Syst Rev. 2018-2-6
Health Technol Assess. 2006-9
Cochrane Database Syst Rev. 2020-10-19
Innovation (Camb). 2024-10-21
Clin Transl Med. 2024-11
Nucleic Acids Res. 2025-1-6
Int J Mol Sci. 2024-8-31
Nat Rev Immunol. 2024-7
Nat Rev Immunol. 2024-9