Comprehensive Metabolic Profiling and Genome-wide Analysis Reveal Therapeutic Modalities for Hepatocellular Carcinoma.
Comprehensive Metabolic Profiling and Genome-wide Analysis Reveal Therapeutic Modalities for Hepatocellular Carcinoma.
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综合代谢谱和全基因组分析揭示了肝细胞癌的治疗方式
DOI：
10.34133/research.0036
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Xia J
中科院分区：
文献类型：
--
作者：
Qi F;Li J;Qi Z;Zhang J;Zhou B;Yang B;Qin W;Cui W;Xia J
了解肝细胞癌 (HCC) 代谢重编程的细节对于改善治疗分层至关重要。通过多组学分析和跨队列验证来调查 4 个队列中 562 名 HCC 患者的代谢失调情况。基于已识别的动态网络生物标志物，鉴定了227个重要代谢基因，总共343名HCC患者被分为4个具有不同代谢特征的异质代谢簇：簇1，丙酮酸亚型，与丙酮酸代谢上调相关；簇1，丙酮酸亚型，与丙酮酸代谢上调相关；簇1，丙酮酸亚型，与丙酮酸代谢上调相关。簇 2，氨基酸亚型，以氨基酸代谢失调为参考；集群3，混合亚型，其中脂质代谢、氨基酸代谢和聚糖代谢失调；第 4 组是糖酵解亚型，与碳水化合物代谢失调有关。这 4 个集群表现出不同的预后、临床特征和免疫细胞浸润，并通过其他 3 个独立队列的基因组改变、转录组学、代谢组学和免疫细胞谱进一步验证。此外，不同簇对代谢抑制剂的敏感性因其代谢特征而异。重要的是，簇2在肿瘤组织中富含免疫细胞，尤其是表达程序性细胞死亡蛋白1（PD-1）的细胞，这可能是由于色氨酸代谢紊乱所致，并且可能从PD-1治疗中获益更多。总之，我们的结果表明 HCC 的代谢异质性，使得根据特定的代谢特征精确有效地治疗 HCC 患者成为可能。
Understanding the details of metabolic reprogramming in hepatocellular carcinoma (HCC) is critical to improve stratification for therapy. Both multiomics analysis and cross-cohort validation were performed to investigate the metabolic dysregulation of 562 HCC patients from 4 cohorts. On the basis of the identified dynamic network biomarkers, 227 substantial metabolic genes were identified and a total of 343 HCC patients were classified into 4 heterogeneous metabolic clusters with distinct metabolic characteristics: cluster 1, the pyruvate subtype, associated with upregulated pyruvate metabolism; cluster 2, the amino acid subtype, with dysregulated amino acid metabolism as the reference; cluster 3, the mixed subtype, in which lipid metabolism, amino acid metabolism, and glycan metabolism are dysregulated; and cluster 4, the glycolytic subtype, associated with the dysregulated carbohydrate metabolism. These 4 clusters showed distinct prognoses, clinical characteristics and immune cell infiltrations, which was further validated by genomic alterations, transcriptomics, metabolomics, and immune cell profiles in the other 3 independent cohorts. Besides, the sensitivity of different clusters to metabolic inhibitors varied depending on their metabolic features. Importantly, cluster 2 is rich in immune cells in tumor tissues, especially programmed cell death protein 1 (PD-1)-expressing cells, which may be due to the tryptophan metabolism disorders, and potentially benefiting more from PD-1 treatment. In conclusion, our results suggest the metabolic heterogeneity of HCC and make it possible to treat HCC patients precisely and effectively on specific metabolic characteristics.
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影响因子：
16.6
作者：
Hama N;Totoki Y;Miura F;Tatsuno K;Saito-Adachi M;Nakamura H;Arai Y;Hosoda F;Urushidate T;Ohashi S;Mukai W;Hiraoka N;Aburatani H;Ito T;Shibata T
通讯作者：
Shibata T
癌症基因组地图集中的致癌信号通路。
影响因子：
64.5
作者：
Sanchez-Vega F;Mina M;Armenia J;Chatila WK;Luna A;La KC;Dimitriadoy S;Liu DL;Kantheti HS;Saghafinia S;Chakravarty D;Daian F;Gao Q;Bailey MH;Liang WW;Foltz SM;Shmulevich I;Ding L;Heins Z;Ochoa A;Gross B;Gao J;Zhang H;Kundra R;Kandoth C;Bahceci I;Dervishi L;Dogrusoz U;Zhou W;Shen H;Laird PW;Way GP;Greene CS;Liang H;Xiao Y;Wang C;Iavarone A;Berger AH;Bivona TG;Lazar AJ;Hammer GD;Giordano T;Kwong LN;McArthur G;Huang C;Tward AD;Frederick MJ;McCormick F;Meyerson M;Cancer Genome Atlas Research Network;Van Allen EM;Cherniack AD;Ciriello G;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
血清LAG-3预测跨性质化学栓塞患者的肝细胞癌患者的结果和治疗反应。
影响因子：
7.3
作者：
Guo M;Qi F;Rao Q;Sun J;Du X;Qi Z;Yang B;Xia J
通讯作者：
Xia J
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network