Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment
Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment
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DOI：
10.1111/febs.15587
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发表时间：
2020-10-22
期刊：
影响因子：
5.4
通讯作者：
Holzhuetter, Hermann-Georg
中科院分区：
文献类型：
--
作者：
Berndt, Nikolaus;Eckstein, Johannes;Holzhuetter, Hermann-Georg
代谢重编程是癌细胞的一个特征，但没有针对所有肿瘤的独特代谢程序。遗传和基因表达研究揭示了异质性间和肿瘤内的代谢酶和膜转运蛋白的模式。这种异质性的功能含义往往仍然难以捉摸。在这里，我们应用系统生物学的方法来获得一个全面的和定量的图片代谢变化在个别肝细胞癌（HCC）。我们使用质谱法测定的10例人类HCC和邻近非癌组织样本中的蛋白质强度谱来校准Hepatokin 1，这是一种复杂的肝脏代谢数学模型。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小时曲线。尽管肿瘤间存在较大的变异性，但肿瘤中葡萄糖摄取和葡萄糖释放的普遍趋势是下调。这一发现引起了对瓦尔堡效应决定HCC代谢表型的质疑。所有肿瘤均包含升高的β-氧化速率。发现尿素合成持续下调，但由于谷氨酰胺合成增加而不损害肿瘤的氨解毒能力。最大的肿瘤间异质性被发现的摄取和释放的乳酸和细胞糖原含量的大小。与观察到的代谢异质性一致，个体肝癌对二甲双胍药物治疗的易感性存在很大差异。总之，我们的方法提供了一个全面的和定量的表征HCC代谢，可能铺平了道路的计算先验评估的药物治疗靶向HCC的代谢过程。
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 beta-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.