Tang Xun, Jiang Ning, Kou Yingying, Cheng Shan, Yan Feng
Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China.
Jiangsu Key Laboratory of Molecular and Translational Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China.
Mol Ther Oncol. 2025 Mar 7;33(2):200963. doi: 10.1016/j.omton.2025.200963. eCollection 2025 Jun 18.
Metabolic reprogramming is an emerging hallmark and promising therapeutic target in cancer, fueling malignant cells and regulating the tumor microenvironment as a metabolic checkpoint. Triple-negative breast cancer (TNBC), an aggressive subtype with poor prognosis, is marked by high recurrence rates and chemotherapy resistance. However, the metabolic heterogeneity and cell-specific metabolic profiles in TNBC remain underexplored. In this study, we analyzed the expression and prognostic impact of 87 metabolic pathways involving 1,668 genes, identifying 104 candidate metabolic checkpoint genes. Using consensus clustering, we uncovered two distinct metabolic subclusters of TNBC patients that exhibited significant differences in survival. We further characterized the differentially expressed genes, mutation profiles, and microenvironmental features between these two clusters. Additionally, -omics analysis of single-cell RNA sequencing revealed that , a gene specifically expressed in malignant cells, functioned as a cell-autonomous metabolic reprogramming factor. We validated that promotes the proliferation, migration, and survival of TNBC cells , driven by dysregulated glucose and lipid metabolism. These processes were mediated, at least in part, through the activation of the signaling pathway. This study highlights the metabolic heterogeneity in TNBC and identifies as a pro-tumor factor, suggesting it as a potential novel therapeutic target.
代谢重编程是癌症中一个新出现的特征和有前景的治疗靶点，它为恶性细胞提供能量并作为代谢检查点调节肿瘤微环境。三阴性乳腺癌（TNBC）是一种侵袭性亚型，预后较差，其特点是复发率高和对化疗耐药。然而，TNBC中的代谢异质性和细胞特异性代谢谱仍未得到充分研究。在本研究中，我们分析了涉及1668个基因的87条代谢途径的表达及其对预后的影响，确定了104个候选代谢检查点基因。通过共识聚类，我们发现了TNBC患者的两个不同的代谢亚群，它们在生存率上表现出显著差异。我们进一步对这两个亚群之间差异表达的基因、突变谱和微环境特征进行了表征。此外，单细胞RNA测序的组学分析表明，一个在恶性细胞中特异性表达的基因，作为一种细胞自主代谢重编程因子发挥作用。我们验证了该基因通过失调的葡萄糖和脂质代谢促进TNBC细胞的增殖、迁移和存活。这些过程至少部分是通过激活信号通路介导的。本研究突出了TNBC中的代谢异质性，并确定该基因是一种促肿瘤因子，提示它是一个潜在的新型治疗靶点。
