Abou Khouzam Raefa, Chouaib Salem, Iqbal Mohammad Askandar
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates.
College of Medicine, Gulf Medical University, Ajman, United Arab Emirates.
Mol Oncol. 2025 Jun;19(6):1725-1736. doi: 10.1002/1878-0261.13762. Epub 2024 Dec 27.
Hypoxia is known to induce reprogramming of glucose metabolism in cancer. However, the impact of hypoxia on global metabolism remains poorly understood. Here, using the systems approach, we evaluated the potential crosstalk between hypoxia and global metabolism using data from > 2000 breast tumors. Tumor samples were scored for hypoxia and 90 metabolic pathways, and these metrics were subjected to an analysis pipeline. Hypoxia showed a very strong association with metabolic aggression and an overall contextual relationship with metabolism. Out of three (M1, M2, and M3) metabolic types in breast cancer, M3 exhibited the strongest relationship with hypoxia; that is, high hypoxic tumors were also metabolically deregulated. Further, the overall correlation pattern between hypoxia and metabolic pathway scores was specific to each type, with M1 showing maximal sensitivity to hypoxia, followed by M2 and then M3. Experimental validation using metabolic inhibitors on cell lines with high or low hypoxia scores further confirmed the metabolic type-dependence of hypoxia. In addition, evaluation of the impact of hypoxia on cancer pathways other than metabolic ones revealed a potential role of hypoxia in immune evasive characteristic of M3 tumors. Overall, the results suggest a complex interplay between hypoxia and metabolism in the context of human breast tumors, with potential implications for both basic cancer biology and breast cancer therapy.
已知缺氧会诱导癌症中葡萄糖代谢的重编程。然而，缺氧对整体代谢的影响仍知之甚少。在这里，我们使用系统方法，利用来自2000多个乳腺肿瘤的数据评估了缺氧与整体代谢之间的潜在相互作用。对肿瘤样本进行缺氧和90种代谢途径评分，并对这些指标进行分析流程。缺氧与代谢侵袭以及与代谢的整体背景关系密切相关。在乳腺癌的三种（M1、M2和M3）代谢类型中，M3与缺氧的关系最为密切；也就是说，高缺氧肿瘤在代谢上也失调。此外，缺氧与代谢途径评分之间的整体相关模式因每种类型而异，M1对缺氧表现出最大敏感性，其次是M2，然后是M3。使用代谢抑制剂对缺氧评分高或低的细胞系进行实验验证，进一步证实了缺氧对代谢类型的依赖性。此外，评估缺氧对代谢以外的癌症途径的影响，揭示了缺氧在M3肿瘤免疫逃逸特征中的潜在作用。总体而言，结果表明在人类乳腺肿瘤的背景下，缺氧与代谢之间存在复杂的相互作用，这对基础癌症生物学和乳腺癌治疗都有潜在影响。
