Human-correlated genetic HCC organoid models identify combination therapy for precision medicine

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer related mortality worldwide. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulated progressive driver mutations, with hepatocytes the most likely cell of origin. However, the landscape of driver mutations in HCC is independent of the underlying aetiologies. Despite an increasing range of systemic treatment options for advanced HCC outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC. We generated over twenty-five new genetically-driven in vivo and in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance, and metastasis to distant organs. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with histopathology. In a proof-of-principle analysis, we verified response to standard of care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not been linked to HCC treatment before. Cladribine acts in a highly effective subtype-specific manner in combination with standard of care therapy. Overall design: Organoids derived from 3 GEMM murine models of HCC. Early and late passages, some taken from different mice of the same GEMM background

肝细胞癌（Hepatocellular carcinoma, HCC）是原发性肝癌最常见的类型，也是全球范围内癌症相关死亡的主要诱因之一。肝细胞癌通常发生于慢性肝病背景之上，此类慢性肝病由一系列易感诱因引发。肿瘤发生由积累了进行性驱动突变的克隆扩增所驱动，肝细胞是最可能的起源细胞。然而，肝细胞癌的驱动突变谱与潜在病因无关。尽管晚期肝细胞癌的系统性治疗选择日益增多，但患者预后仍存在显著异质性，且整体预后通常较差。最新研究数据表明，药物疗效取决于疾病病因与遗传改变情况。因此，在具有人类相关性的临床前模型中探索疾病亚型，对于推进肝细胞癌的精准医学研究至关重要。本研究构建了超过25种全新的、遗传背景驱动的体内（in vivo）与体外（in vitro）肝细胞癌模型。本研究构建的模型涵盖了人类肝细胞癌的多种特征，包括克隆起源、组织病理学表型以及远端器官转移能力。我们将小鼠模型的转录组数据与人类肝细胞癌数据进行整合，鉴定出4个共有的人-鼠亚型簇。这些亚型簇具有独特的转录组特征，且与组织病理学表型相符。在一项原理验证分析中，我们验证了模型对标准治疗方案的响应，并通过体内外联动的实验管线，鉴定出一种此前未被关联于肝细胞癌治疗的极具潜力的治疗候选药物——克拉屈滨（cladribine）。克拉屈滨与标准治疗方案联用时，可针对特定亚型发挥高效治疗作用。整体实验设计：本研究使用3种肝细胞癌基因工程小鼠模型（Genetically Engineered Mouse Model, GEMM）构建类器官，涵盖早期与晚期传代样本，部分样本取自同一GEMM背景下的不同小鼠。