Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

IF 20.1 1区 医学 Q1 ONCOLOGY Cancer Communications Pub Date : 2023-12-24 DOI:10.1002/cac2.12513
Weiren Liu, Huqiang Wang, Qianfu Zhao, Chenyang Tao, Weifeng Qu, Yushan Hou, Run Huang, Zimei Sun, Guiqi Zhu, Xifei Jiang, Yuan Fang, Jun Gao, Xiaoling Wu, Zhixiang Yang, Rongyu Ping, Jiafeng Chen, Rui Yang, Tianhao Chu, Jian Zhou, Jia Fan, Zheng Tang, Dong Yang, Yinghong Shi
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Abstract

Background

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.

Methods

We performed integrated multiomics analysis in 116 iCCA samples, including whole-exome sequencing, bulk RNA-sequencing and proteome analysis. Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells.

Results

Three metabolic subtypes (S1-S3) with subtype-specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune-suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT-rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype-specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen-activated protein kinase (MAPK) signaling.

Conclusion

Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.

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多组学分析揭示了代谢亚型,并确定二酰甘油激酶α(DGKA)是肝内胆管癌的潜在治疗靶点。
背景:肝内胆管癌(iCCA)是一种高度异质性的致死性肝胆肿瘤,治疗策略很少。肿瘤细胞的代谢重编程在肿瘤的发展过程中起着至关重要的作用,而 iCCA 的代谢分子分类在很大程度上是未知的。在此,我们进行了综合多组学分析和代谢分类,以描述iCCA患者代谢特征的差异,希望能为理解和治疗iCCA提供一个新的视角:我们对116份iCCA样本进行了综合多组学分析,包括全外显子组测序、大量RNA测序和蛋白质组分析。根据非负矩阵因式分解法和人类基因组尺度代谢模型中代谢基因的蛋白质丰度,确定了iCCA的代谢亚型。生存和预后基因分析用于比较不同代谢亚型的总生存率(OS)差异。通过细胞增殖分析、5-乙炔基-2'-脱氧尿苷(EdU)检测、集落形成检测、RNA测序和Western印迹等方法研究了iCCA细胞中二酰甘油激酶α(DGKA)的分子机制:结果:发现了三种代谢亚型(S1-S3),它们具有iCCA亚型特异性生物标志物。这些代谢亚型具有不同的预后、代谢特征、免疫微环境和基因改变。生存率最差的S2亚型表现出一些特殊代谢过程的激活、免疫抑制微环境和Kirsten大鼠肉瘤病毒癌基因同源体(KRAS)/富AT交互结构域1A(ARID1A)突变。在S2亚型特异性上调蛋白中,DGKA被进一步鉴定为iCCA的潜在药物靶点,它通过增强磷脂酸(PA)代谢和激活丝裂原活化蛋白激酶(MAPK)信号传导促进细胞增殖:通过多组学分析,我们确定了iCCA的三种代谢亚型,发现S2亚型的生存率最差。我们进一步确定了DGKA是S2亚型的潜在靶点。
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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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