Huang Hongting, Wu Liang, Lu Li, Zhang Zijie, Qiu Bijun, Mo Jialin, Luo Yi, Xi Zhifeng, Feng Mingxuan, Wan Ping, Zhu Jianjun, Yu Dingye, Wu Wei, Tan Kezhe, Liu Jiangbin, Sheng Qingfeng, Xu Ting, Huang Jinyan, Lv Zhibao, Tang Yujie, Xia Qiang
Department of Liver Surgery, Renji Hospital, School of Medicine , Shanghai Jiaotong University , Shanghai , China.
Research Center of Translational Medicine, Shanghai Children's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology , Shanghai Jiaotong University School of Medicine , Shanghai , China.
Hepatology. 2023 Jun 1;77(6):1911-1928. doi: 10.1002/hep.32775. Epub 2023 Mar 29.
Hepatoblastoma (HB) is the predominant type of childhood liver cancer. Treatment options for the clinically advanced HB remain limited. We aimed to dissect the cellular and molecular basis underlying HB oncogenesis and heterogeneity at the single-cell level, which could facilitate a better understanding of HB at both the biological and clinical levels.
Single-cell transcriptome profiling of tumor and paired distal liver tissue samples from five patients with HB was performed. Deconvolution analysis was used for integrating the single-cell transcriptomic profiles with the bulk transcriptomes of our HB cohort of post-neoadjuvant chemotherapy tumor samples. A single-cell transcriptomic landscape of early human liver parenchymal development was established for exploring the cellular root and hierarchy of HB oncogenesis. As a result, seven distinct tumor cell subpopulations were annotated, and an effective HB subtyping method was established based on their compositions. A HB tumor cell hierarchy was further revealed to not only fit with the classical cancer stem cell (CSC) model but also mirror the early human liver parenchymal development. Moreover, FACT inhibition, which could disrupt the oncogenic positive feedback loop between MYC and SSRP1 in HB, was identified as a promising epigenetic-targeted therapeutic strategy against the CSC-like HB1-Pro-like1 subpopulation and its related high-risk "Pro-like1" subtype of HB.
Our findings illustrate the cellular architecture and developmental trajectories of HB via integrative bulk and single-cell transcriptome analyses, thus establishing a resourceful framework for the development of targeted diagnostics and therapeutics in the future.
肝母细胞瘤（HB）是儿童期肝癌的主要类型。临床晚期HB的治疗选择仍然有限。我们旨在剖析HB肿瘤发生和异质性在单细胞水平上的细胞和分子基础，这有助于在生物学和临床层面更好地理解HB。
对5例HB患者的肿瘤及配对的远端肝组织样本进行了单细胞转录组分析。反卷积分析用于将单细胞转录组图谱与我们的新辅助化疗后肿瘤样本的HB队列的整体转录组进行整合。建立了早期人类肝脏实质发育的单细胞转录组图谱，以探索HB肿瘤发生的细胞根源和层次结构。结果，注释了7个不同的肿瘤细胞亚群，并基于它们的组成建立了一种有效的HB亚型分类方法。进一步揭示了HB肿瘤细胞层次结构不仅符合经典的癌症干细胞（CSC）模型，而且反映了早期人类肝脏实质发育。此外，FACT抑制可破坏HB中MYC和SSRP1之间的致癌正反馈环，被确定为针对CSC样HB1-Pro样1亚群及其相关的高风险“Pro样1”亚型HB的一种有前景的表观遗传靶向治疗策略。
我们的研究结果通过整合整体和单细胞转录组分析阐明了HB的细胞结构和发育轨迹，从而为未来开发靶向诊断和治疗方法建立了一个丰富的框架。
