Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.
Institute of Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.
FEBS J. 2021 Apr;288(7):2332-2346. doi: 10.1111/febs.15587. Epub 2020 Oct 22.
Metabolic reprogramming is a characteristic feature of cancer cells, but there is no unique metabolic program for all tumors. Genetic and gene expression studies have revealed heterogeneous inter- and intratumor patterns of metabolic enzymes and membrane transporters. The functional implications of this heterogeneity remain often elusive. Here, we applied a systems biology approach to gain a comprehensive and quantitative picture of metabolic changes in individual hepatocellular carcinoma (HCC). We used protein intensity profiles determined by mass spectrometry in samples of 10 human HCCs and the adjacent noncancerous tissue to calibrate Hepatokin1, a complex mathematical model of liver metabolism. We computed the 24-h profile of 18 metabolic functions related to carbohydrate, lipid, and nitrogen metabolism. There was a general tendency among the tumors toward downregulated glucose uptake and glucose release albeit with large intertumor variability. This finding calls into question that the Warburg effect dictates the metabolic phenotype of HCC. All tumors comprised elevated β-oxidation rates. Urea synthesis was found to be consistently downregulated but without compromising the tumor's capacity for ammonia detoxification owing to increased glutamine synthesis. The largest intertumor heterogeneity was found for the uptake and release of lactate and the size of the cellular glycogen content. In line with the observed metabolic heterogeneity, the individual HCCs differed largely in their vulnerability against pharmacological treatment with metformin. Taken together, our approach provided a comprehensive and quantitative characterization of HCC metabolism that may pave the way for a computational a priori assessment of pharmacological therapies targeting metabolic processes of HCC.
代谢重编程是癌细胞的一个特征，但并非所有肿瘤都具有独特的代谢程序。遗传和基因表达研究揭示了代谢酶和膜转运体在肿瘤内和肿瘤间存在异质性。这种异质性的功能意义仍然常常难以捉摸。在这里，我们应用系统生物学方法来全面、定量地描述单个肝细胞癌 (HCC) 的代谢变化。我们使用质谱法测定的 10 个人 HCC 样本及其相邻非癌组织中的蛋白质强度谱来校准 Hepatokin1，这是一种肝脏代谢的复杂数学模型。我们计算了与碳水化合物、脂质和氮代谢相关的 18 种代谢功能的 24 小时谱。尽管肿瘤间存在很大的变异性，但所有肿瘤都普遍存在葡萄糖摄取和释放下调的趋势。这一发现质疑了沃伯格效应决定 HCC 代谢表型的说法。所有肿瘤的β-氧化率都升高。发现尿素合成始终下调，但由于谷氨酰胺合成增加，肿瘤的氨解毒能力不受影响。乳酸摄取和释放以及细胞糖原含量的大小是肿瘤间最大的异质性。与观察到的代谢异质性一致，个体 HCC 在对二甲双胍等药物治疗的敏感性方面存在很大差异。总之，我们的方法提供了对 HCC 代谢的全面和定量描述，可能为针对 HCC 代谢过程的药物治疗的计算先验评估铺平道路。
