Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Kay Laboratory of Quality Research in Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, China.
Faculty of Health Sciences, University of Macau, Taipa, Macau SAR 999078, China.
Cells. 2024 Oct 17;13(20):1721. doi: 10.3390/cells13201721.
Aging is an important risk factor for tumorigenesis. Metabolic reprogramming is a hallmark of both aging and tumor initiation. However, the manner in which the crosstalk between aging and metabolic reprogramming affects the tumor microenvironment (TME) to promote tumorigenesis was poorly explored. We utilized a computational approach proposed by our previous work, MMPC (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to characterize aging-related metabolic plasticity events using pan-cancer bulk RNA-seq data. Our analysis revealed a high degree of metabolically organized heterogeneity across 17 aging-related cancer types. In particular, a higher degree of several energy generation pathways, i.e., glycolysis and impaired oxidative phosphorylation, was observed in older patients. Similar phenomena were also found via single-cell RNA-seq analysis. Furthermore, those energy generation pathways were found to be weakened in activated T cells and macrophages, whereas they increased in exhausted T cells, immunosuppressive macrophages, and Tregs in older patients. It was suggested that aging-induced metabolic switches alter glucose utilization, thereby influencing immune function and resulting in the remodeling of the TME. This work offers new insights into the associations between tumor metabolism and the TME mediated by aging, linking with novel strategies for cancer therapy.
衰老是肿瘤发生的一个重要危险因素。代谢重编程是衰老和肿瘤起始的标志。然而，衰老和代谢重编程之间的相互作用以何种方式影响肿瘤微环境（TME）以促进肿瘤发生，这方面的研究还很不完善。我们利用了我们之前工作中提出的一种计算方法 MMPC（通过通路成对比较来模拟代谢可塑性），使用泛癌症批量 RNA-seq 数据来描述与衰老相关的代谢可塑性事件。我们的分析揭示了 17 种与衰老相关的癌症类型之间存在高度代谢组织异质性。特别是，在老年患者中观察到更高程度的几种能量生成途径，即糖酵解和氧化磷酸化受损。单细胞 RNA-seq 分析也发现了类似的现象。此外，这些能量生成途径在激活的 T 细胞和巨噬细胞中被削弱，而在老年患者中耗尽的 T 细胞、免疫抑制性巨噬细胞和 Tregs 中增加。这表明衰老诱导的代谢转换改变了葡萄糖的利用，从而影响免疫功能并导致 TME 的重塑。这项工作为肿瘤代谢与衰老介导的 TME 之间的关联提供了新的见解，为癌症治疗的新策略提供了依据。
