肿瘤瞭望消化时讯-首页

首页 > 正文

EASL 2025 丨中国智慧闪耀欧洲肝癌峰会，八大摘要抢先看！（基础研究篇）

肿瘤瞭望消化时讯发表时间：2025-02-20 16:35:37

编者按：当地时间2025年2月20日至22日，2025年欧洲肝脏研究学会（EASL）肝癌峰会将于法国巴黎隆重召开。作为肝癌领域的重要学术交流平台，中国学者将在这一国际舞台上展示多项重磅研究成果。从早期诊断到精准治疗，从基础研究到临床转化，中国团队以独特视角和创新方法，为全球肝癌防治贡献了不可忽视的“中国智慧”。

《肿瘤瞭望消化时讯》特别整理中国学者在EASL肝癌峰会上的基础研究摘要内容，带您一览中国肝癌研究的最新突破与未来方向。

摘要号：PO2-01

FOXO1在肝细胞癌移植后复发中的作用：诊断与治疗靶点研究The Role of FOXO1 in Post-Transplant Recurrence of Hepatocellular Carcinoma: A Study on Diagnostic and Therapeutic Targets作者：Xiao Xu（浙江大学）

背景：肝细胞癌（HCC）是中国高发且致死率较高的恶性肿瘤，尽管肝移植是治疗HCC的有效方法，但肿瘤复发仍是一个重大挑战。本研究旨在探讨FOXO1与HCC患者肝移植预后的临床相关性，并在动物模型中探索一种纳米复合物的治疗潜力。

方法：我们分析了HCC患者（n=259）的肝移植样本组织芯片，还构建了一种携带FOXO1的酯酶响应性阳离子脂质体包被纳米复合物（靶向肝脏），评估其在体内对肝移植后肿瘤复发的影响。

结果：肝移植组织芯片分析显示，与FOXO1高表达的患者相比，FOXO1低表达的受试者无瘤生存期（P=0.010）和总生存期（P=0.019）显著缩短。与对照组相比，使用纳米复合物治疗后，小鼠的肿瘤体积显著减小。

结论：FOXO1低表达是HCC患者肝移植后复发的危险因素。FOXO1通过减轻肝脏缺血再灌注损伤诱导的氧化应激和炎症反应，从而抑制HCC进展。

摘要原文

Background and aims: Hepatocellular carcinoma (HCC) is a highly prevalent and deadly malignancy in China. Although liver transplantation is the most effective treatment for HCC, tumor recurrence remains a significant challenge. Identifying precise diagnostic and therapeutic targets for post-transplant recurrence is crucial for improving HCC outcomes. This study aims to investigate the clinical association between FOXO1 and liver transplant outcomes in HCC patients and to explore the therapeutic potential of an esterase-responsive cationic liposome-coated nanocomplex targeting the liver in animal models.

Method: We analyzed a tissue microarray of liver transplant samples from HCC patients (n = 259) to elucidate the correlation between FOXO1 expression and clinical parameters. We then constructed an esterase-responsive cationic liposome-coated nanocomplex carrying FOXO1, targeting the liver, and evaluated its effects in vivo on tumor recurrence post-transplant.

Results: Analysis of the liver transplant tissue microarray revealed that recipients with low FOXO1 expression had significantly shorter tumor-free survival (P = 0.010) and overall survival (P = 0.019) compared to those with high FOXO1 expression. Animal experiments showed that hepatic ischemiareperfusion injury (IRI) induced changes in key inflammatory (TNF-α and IL-6) and oxidative stress proteins (Nrf-2 and HO-1), promoting tumor growth. Treatment with the liver-targeted FOXO1 esteraseresponsive cationic liposome-coated nanocomplex significantly reduced tumor size in mice post-IRI compared to controls. Additionally, alanine aminotransferase and aspartate aminotransferase levels and liver histology (HE staining) indicated reduced IRI in treated mice. The nanocomplex treatment also decreased inflammatory protein expression and increased oxidative stress protein expression in the liver.

Conclusion: Low FOXO1 expression is a risk factor for post-transplant recurrence of HCC. FOXO1 can inhibit HCC progression by mitigating oxidative stress and inflammatory responses induced by hepatic IRI, providing a new strategy for the diagnosis and treatment of tumor recurrence after liver transplantation in HCC patients.

摘要号：PO2-02

HCC中N6-甲基腺苷甲基化与肿瘤免疫微环境的分子表型关联研究

Molecular Phenotypic Linkage Between N6-methyladenosine Methylation and Tumor Immune Microenvironment in Hepatocellular Carcinoma

作者：Feng Zhang（中山大学）

背景：N6-甲基腺苷（m6A）甲基化在抗肿瘤免疫治疗中的关键作用已被熟知。然而，在HCC中，m6A修饰模式与免疫生态系统之间的分子表型关联仍需进一步阐明。

方法：我们定性分析了m6A甲基化的修饰模式，通过系统评估确定了其与免疫表型的关联。通过构建m6A评分，实现了m6A甲基化模式的个体化量化。此外，我们还筛选了候选治疗药物。

结果：我们确定了三种不同的m6A甲基化模式。具体而言，免疫炎症型高m6A评分组以免疫激活和良好预后为特征；低m6A评分表型则表现为基质激活和免疫细胞浸润缺失，与不良预后相关。基于m6A甲基化模式，我们筛选出七种潜在的治疗药物。

结论：本研究在HCC中建立了表观遗传学与抗肿瘤免疫之间的可信联系，揭示了m6A甲基化模式作为免疫治疗生物学指标和预测因子的潜力。

摘要原文

Background and aims: The crucial role of N6 -methyladenosine (m6A) methylation in anti-tumor immunity and immunotherapy has been broadly depicted. However, the molecular phenotypic linkages between m6A modification pattern and immunological ecosystem are expected to be disentangled in hepatocellular carcinoma (HCC), for immunotherapeutic unresponsiveness circumvention and combination with promising drug agents.

Method: Modification patterns of m6A methylation were qualitatively dissected according to the largescale HCC samples profiling. We then determined the immune phenotypic linkages by systematically evaluating their tumor microenvironment composition, immune/stromal-relevant signature, immune checkpoints correlation and prognostic value. Individual quantification of m6A methylation pattern was achieved by m6Ascore construction, intensified by longitudinal single-cell analysis of immunotherapy cohort and validated by the transcriptomic profiles of our in-hospital GDPH-HCC cohort. Candidate therapeutic agents were also screened out. Results: Three distinct m6A methylation patterns were determined in high accordance with inflamed-, excluded- and desert- immunophenotype. To be precise, Immune-inflamed high-m6Ascore group was characterized by activated immunity with favorable prognosis. Stromal activation and absence of immune cell infiltration were observed in low-m6Ascore phenotype, linked to impaired outcome. Patients with low-m6Ascore demonstrated diminished responses and clinical benefits for cohorts receiving immunotherapy. The above credible linkage between m6A methylation pattern and tumor immune microenvironment was robustly validated in our GDPH-HCC cohort. Single-cell dynamic change of m6A methylation level in exhausted CD8 T cell and fibroblast was depicted in immunotherapy cohort fore and art. Derived from m6A methylation pattern, seven potential frontline drug agents were recognized as promising choice for high-m6Ascore patients.

Conclusion: Our work bridged the credible linkage between epigenetics and anti-tumor immunity in HCC, unraveling m6A modification pattern as immunological indicator and predictor for immunotherapy. Individualized m6Ascore facilitated strategic choices to maximize therapy-responsive possibility

摘要号：PO3-05

靶向亮氨酰-tRNA合成酶1的亮氨酸饮食可增强N-糖基化生物合成翻译并克服化疗耐药性

Leucine diet targeting leucyl-tRNA synthetase 1 enhances N-glycan biosynthesis translation and overcomes chemoresistance

作者：Liu Haining（山东大学齐鲁医院）

背景：肝内胆管癌（ICC）容易转移且对化疗反应低，其潜在机制尚不明确。本研究发现了ICC中选择性低反应状态，并阐明了其调控机制，为增强化疗疗效提供了潜在治疗靶点的见解。

方法：通过细胞培养、条件性基因敲除小鼠模型和两种水动力转染ICC模型，进行了功能分析和机制研究，并在体内评估了化疗单独使用或联合亮氨酸补充/抑制剂的效果。

结果：亮氨酰-tRNA合成酶1（LARS1）在ICC患者中显著减少，尤其是在晚期阶段，其表达与患者生存率呈正相关。机制上，LARS1缺陷增强了ABCC1介导的化疗耐药。外源性亮氨酸补充可上调LARS1的表达，并显著提高ICC临床前小鼠模型中化疗的疗效。

结论：我们的研究阐明了在mRNA翻译层面对N-糖基化的调控机制，提供了一种能够提高化疗疗效的饮食-药物联合策略。摘要原文（滑动查看完整内容）Background and aims: Intrahepatic cholangiocarcinoma (ICC) is characterised by high metastatic potential and poor response rates to chemotherapy, with the underlying mechanisms remaining largely elusive. Our study identifies a selective hypotranslation status in ICC and elucidates the regulatory mechanisms, offering insights into potential therapeutic targets to enhance chemotherapy efficacy.

Method: Proteomic data and tumour specimens from ICC patients were utilised to identify key proteins associated with translation and prognosis in ICC. Functional analyses and mechanistic studies were conducted using cell culture, conditional knockout mouse model, and two hydrodynamic transfection ICC models. The effectiveness of chemotherapy, alone or in combination with leucine supplementation or chemical inhibitors, was assessed in vivo. Results: Leucyl-tRNA Synthetase 1 (LARS1) is markedly reduced in intrahepatic cholangiocarcinoma (ICC), particularly in advanced stages, and its expression is positively associated with patient survival. Using cell lines and diverse ICC models, we demonstrate that LARS1 plays a pivotal role in regulating tumour progression and resistance to chemotherapy. Mechanistically, LARS1 deficiency suppresses the translation of ALG3, ALG12, and RFT1 mRNAs, leading to reduced N-glycosylation of ABCC1 at N929. This alteration enhances ABCC1's function in mediating chemoresistance. Remarkably, exogenous leucine supplementation safely upregulates LARS1 expression and significantly improves the efficacy of chemotherapy in ICC preclinical mouse models.

Conclusion: Our findings uncover new insight into the selective mRNA hypotranslation observed in ICC and mechanisms regulating N-glycosylation at the layer of mRNA translation, providing a diet-drug combined strategy to improve chemotherapy efficacy. These results highlight a promising diet-drug combination strategy to enhance the efficacy of chemotherapy.

摘要号：PO4-20

小鼠HCC模型中微血管结构的高分辨率定量重建

High-resolution quantitative reconstruction of microvascular architectures in mouse hepatocellular carcinoma models

作者：Yan Zhao（西安国际医学中心医院）

背景：肝脏血管化改变在HCC的发展中起着关键作用，但相关研究仍不足。本研究提供了野生型小鼠和HCC小鼠模型中肝脏血管特征及结构的高分辨率定量解剖数据。

方法：向C57BL/6小鼠注射Akt/Ras或睡美人转座子以诱导HCC，后对野生型小鼠和Akt/Ras小鼠的肝组织进行染色。利用先进的高清荧光显微光学断层扫描技术，对野生型小鼠和Akt/Ras HCC小鼠的肝脏进行了高精度微血管可视化分析。

结果：正常和HCC肝组织的切片体积分别为204.8 mm³和212.8 mm³。Akt/Ras HCC小鼠组织中相关的微血管系统扭曲、紊乱，并被肿瘤结节压迫。癌旁肝硬化组织中肝窦中心血管的半径显著高于正常组织（36.8 vs. 66.4 μm，P<0.001）；然而，癌旁肝硬化组织的肝窦密度较低（154.3 vs. 496 μm-2，P<0.001）。

结论：本研究深入探究了正常肝脏微血管结构以及肝硬化和HCC病例中的血管改变，补充了关于肝脏形态和生理学的科学见解。摘要原文（滑动查看完整内容）Background and aims: Alterations in liver vascularization play a remarkable role in liver disease development, including hepatocellular carcinoma (HCC), but remain understudied. This study evaluated the hepatic microvascular imaging method and provided high-resolution quantitative anatomical data on the characteristics and architecture of liver vasculature in wild-type (WT) mice and HCC mouse models.

Method: C57BL/6 mice were injected with Akt/Ras or Sleeping Beauty transposon to induce HCC. Liver tissues from normal and Akt/Ras mice underwent hematoxylin and eosin, Masson’s trichrome, Ki67, and lymphatic endothelial receptor-1 staining. Using cutting-edge high-definition fluorescence micro-optical sectioning tomography, high-precision microvascular visualization of the liver was performed in WT and Akt/Ras HCC mice.

Results: The sectioned volumes of normal and HCC liver tissues were 204.8 mm3 and 212.8 mm3, respectively. The microvascular systems associated with the tissues of Akt/Ras HCC mice were twisted, disordered, and compressed by tumor nodules. In the four tumor nodules, the path of the hepatic artery was more around the tumor edge, whereas the portal vein occupied the central position and constituted the main blood vessel entering the tumors. The porosity of HCC and paracancerous cirrhotic tissues was significantly less than that of normal tissues. The radii of the central vessels in the hepatic sinusoid of paratumoral cirrhotic tissues were significantly higher than those of normal tissues (36.8 vs. 66.4 μm, P<0.001); however, the hepatic sinusoid density of paratumoral cirrhotic tissues was lower (154.3 vs. 496 μm-2 , P<0.001).

Conclusion: This research provides a deeper understanding of the normal liver microvasculature and alterations in cases of cirrhosis and HCC, which complements scientific insights into liver morphology and physiology. This straightforward research approach involving the novel 3D liver microvasculature can be used in multiscale physiological and pathophysiological studies regarding liver diseases.

摘要号：PO6-07

揭示ZBED4在HCC中的作用：基于泛癌分析及多数据库证据

Unveiling the Role of ZBED4 in Hepatocellular Carcinoma: Evidence From the Pan-cancer Analysis and Multiple Databases

作者：Tongyu Lin（四川省肿瘤医院）

背景：HCC是一种常见且致命的恶性肿瘤，探索新的治疗靶点和策略至关重要。ZBED4在癌症中的作用此前尚未明确。

方法：本研究利用癌症基因组图谱（TCGA）、基因表达综合数据库（GEO）、国际癌症基因组联盟（ICGC）、癌症药物敏感性基因组学（GDSC）数据库及多种网络平台和软件进行数据分析。

结果：研究发现，ZBED4的高表达与多种癌症的不良预后及免疫浸润相关。在HCC中，ZBED4高表达组织中的Treg细胞和中性粒细胞更加富集，而ZBED4低表达组中CD8+ T细胞、活化的CD4+ T细胞、γ/δ T细胞以及活化的NK细胞更为丰富。高ZBED4表达与较差的免疫检查点阻断治疗反应相关，但对化疗和大多数靶向治疗的反应较好。

结论：本研究阐明了ZBED4的特征及其与免疫浸润的密切关系，并强调了其作为HCC预后和治疗潜在生物标志物的重要价值。

摘要原文

Background and aims: Hepatocellular carcinoma (HCC) is a common and deadly malignancy that has proven difficult to treat. Exploring new targets and therapeutic approaches is quite necessary. The role of ZBED4 in cancers was previously unknown.

Method: The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC) and the Genomics of Drug Sensitivity in Cancer (GDSC) database were used. Multiple web platforms and software were employed, including R, GEPIA2.0, GSCALite, and CancerSEA for data analysis. The multiplex immunofluorescence was conducted using human HCC tissue micorarray.

Results: High ZBED4 expression was found to be related to unfavorable prognosis and immune infiltration in a variety of cancers. ZBED4 was involved in numerous cancer pathways, including ferroptosis regulation in HCC. In HCC, Tregs and neutrophils were more prevalent in tissues with high ZBED4 expression, while CD8+ T cells, activated CD4+ T cells, gamma/delta T cells, and activated NK cells were more abundant in the low ZBED4 expression group. High ZBED4 expression correlates with poorer immune checkpoint blocking (ICB) response, but better therapeutic responses to chemotherapy and most targeted therapy in HCC patients. Furthermore, a multi-gene prognostic signature was established and validated in different HCC cohorts. The multiplex immunofluorescence study confirmed ZBED4 is associated with an unfavorable prognosis, exhibiting a negative correlation with CD8+T cells infiltration.

Conclusion: Our study clarifies the characterization of ZBED4 and its close association with immune infiltration and highlights its potential value as a promising biomarker for prognosis and therapy in HCC.