Department of Hematology & Oncology, Jiangbei Campus, The First Affiliated Hospital of Army Medical University, Chongqing, China.
Department of Hepatobiliary Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China.
Clin Transl Med. 2024 Jun;14(6):e1727. doi: 10.1002/ctm2.1727.
The liver is anatomically divided into eight segments based on the distribution of Glisson's triad. However, the molecular mechanisms underlying each segment and its association with hepatocellular carcinoma (HCC) heterogeneity are not well understood. In this study, our objective is to conduct a comprehensive multiomics profiling of the segmentation atlas in order to investigate potential subtypes and therapeutic approaches for HCC.
A high throughput liquid chromatography-tandem mass spectrometer strategy was employed to comprehensively analyse proteome, lipidome and metabolome data, with a focus on segment-resolved multiomics profiling. To classify HCC subtypes, the obtained data with normal reference profiling were integrated. Additionally, potential therapeutic targets for HCC were identified using immunohistochemistry assays. The effectiveness of these targets were further validated through patient-derived organoid (PDO) assays.
A multiomics profiling of 8536 high-confidence proteins, 1029 polar metabolites and 3381 nonredundant lipids was performed to analyse the segmentation atlas of HCC. The analysis of the data revealed that in normal adjacent tissues, the left lobe was primarily involved in energy metabolism, while the right lobe was associated with small molecule metabolism. Based on the normal reference atlas, HCC patients with segment-resolved classification were divided into three subtypes. The C1 subtype showed enrichment in ribosome biogenesis, the C2 subtype exhibited an intermediate phenotype, while the C3 subtype was closely associated with neutrophil degranulation. Furthermore, using the PDO assay, exportin 1 (XPO1) and 5-lipoxygenase (ALOX5) were identified as potential targets for the C1 and C3 subtypes, respectively.
Our extensive analysis of the segmentation atlas in multiomics profiling defines molecular subtypes of HCC and uncovers potential therapeutic strategies that have the potential to enhance the prognosis of HCC.
肝脏根据 Glisson 三联体的分布解剖分为八个节段。然而，每个节段的分子机制及其与肝细胞癌（HCC）异质性的关系尚不清楚。在这项研究中，我们的目标是对分段图谱进行全面的多组学分析，以研究 HCC 的潜在亚型和治疗方法。
采用高通量液相色谱-串联质谱策略全面分析蛋白质组、脂质组和代谢组数据，重点进行节段分辨率的多组学分析。为了对 HCC 亚型进行分类，整合了获得的带有正常参考分析的数据集。此外，还通过免疫组织化学检测鉴定了 HCC 的潜在治疗靶点。通过患者来源的类器官（PDO）检测进一步验证了这些靶点的有效性。
对 8536 种高可信度蛋白质、1029 种极性代谢物和 3381 种非冗余脂质进行了多组学分析，以分析 HCC 的分段图谱。数据分析表明，在正常相邻组织中，左叶主要参与能量代谢，而右叶与小分子代谢有关。根据正常参考图谱，对节段分辨率分类的 HCC 患者进行了三种亚型的划分。C1 亚型表现出核糖体生物发生的富集，C2 亚型表现出中间表型，而 C3 亚型与嗜中性粒细胞脱颗粒密切相关。此外，通过 PDO 检测，发现 exportin 1（XPO1）和 5-lipoxygenase（ALOX5）分别是 C1 和 C3 亚型的潜在治疗靶点。
我们对多组学分析中分段图谱的广泛分析定义了 HCC 的分子亚型，并揭示了潜在的治疗策略，有望改善 HCC 的预后。
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