DataSheet1_Single-cell transcriptomics reveals tumor microenvironment remodeling in hepatocellular carcinoma with varying tumor subclonal complexity.docx

IntroductionThe complexity of tumor cell subclonal structure has been extensively investigated in hepatocellular carcinoma. However, the role of subclonal complexity in reshaping the tumor microenvironment (TME) remains poorly understood.MethodsWe integrated single-cell transcriptome sequencing data from four independent HCC cohorts, involving 30 samples, to decode the associations between tumor subclonal complexity and the TME. We proposed a robust metric to accurately quantify the degree of subclonal complexity for each sample based on discrete copy number variations (CNVs) profiles.ResultsWe found that tumor cells in the high-complexity group originated from the cell lineage with FGB overexpression and exhibited high levels of transcription factors associated with poor survival. In contrast, tumor cells in low-complexity patients showed activation of more hallmark signaling pathways, more active cell-cell communications within the TME and a higher immune activation status. Additionally, cytokines signaling activity analysis suggested a link between HMGB1 expressed by a specific endothelial subtype and T cell proliferation.DiscussionOur study sheds light on the intricate relationship between the complexity of subclonal structure and the TME, offering novel insights into potential therapeutic targets for HCC.

引言：肿瘤细胞亚克隆结构的复杂性在肝细胞癌中已被广泛研究。然而，亚克隆复杂性在重塑肿瘤微环境（TME）中所扮演的角色仍处于理解不足的状态。方法：我们整合了来自四个独立HCC队列的单细胞转录组测序数据，涉及30个样本，以解码肿瘤亚克隆复杂性与其TME之间的关联。我们提出了一种稳健的指标，基于离散拷贝数变异（CNVs）谱，以准确量化每个样本的亚克隆复杂性程度。结果：我们发现高复杂性组中的肿瘤细胞源自FGB高表达的细胞谱系，并表现出与不良预后相关的高水平转录因子。相反，低复杂性患者的肿瘤细胞显示出更多标志性的信号通路激活，TME内更活跃的细胞间通讯以及更高的免疫激活状态。此外，细胞因子信号活性分析表明，特定内皮亚型表达的HMGB1与T细胞增殖之间存在联系。讨论：我们的研究揭示了亚克隆结构复杂性与其TME之间错综复杂的关系，为肝细胞癌（HCC）的潜在治疗靶点提供了新的见解。