A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets
A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets
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DOI：
10.1073/pnas.1912146117
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发表时间：
2020-03-17
影响因子：
11.1
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Liu, Ming;Yan, Qian;Guan, Xin-Yuan
对肿瘤侵袭性和胚胎发育阶段之间关系的临床观察表明，发育信号在癌症的启动和治疗抵抗中具有重要意义。然而，器官发生过程中的动态基因表达和主要的致癌基因驱动因素仍然不清楚，这阻碍了包括人肝细胞癌在内的预后不良肿瘤的有效消除。在这项研究中，人类胚胎干细胞被诱导沿着肝脏谱系分化为成年肝细胞，以模拟体外肝脏的发育。结合肝癌患者的转录数据和肝细胞分化模型，筛选出来自不同肝脏发育阶段和肿瘤组织的活性基因。生物信息学分析和实验分析被用来验证肿瘤亚型特异性的癌胎儿特征和潜在的治疗价值。等级聚类分析显示，存在两种不同癌胚属性的肝癌亚型。这些基因特征及其临床意义在独立的临床队列和癌症基因组图谱数据库中得到了进一步验证。上游激活子分析和功能筛选进一步确定E2F1和Smad3为主要转录调控因子。专门针对癌胎儿驱动的小分子抑制剂广泛下调亚型特异性发育信号，并抑制肿瘤致瘤性。具有不同致癌胎儿特性的肝癌细胞和原发性肝细胞癌肿瘤也显示出对其特定抑制物的选择性易感性。此外，根据亚型特异性生物标记物精确靶向肿瘤启动步骤和驱动事件可能会消除肿瘤进展并提供新的治疗策略。
Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.