Lu Yinghong, Xu Lixia, Chen Weikang, Liu Weixin, Zhang Ying, Zhou Qianying, Wang Na, Zhang Yongxin, Bai Haojie, Xu Shu, Huang Pingmei, Fu Kaili, Xie Wenxuan, Liu Xin, Wang Xueliang, Wong Chi Chun, Kuang Ming, Yu Jun
Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Cancer Discov. 2025 Aug 4;15(8):1630-1648. doi: 10.1158/2159-8290.CD-24-1259.
The signature of the intrahepatic microbiome in multifocal hepatocellular carcinoma (HCC) and its association with genomic alterations remain elusive. In this study, we performed multiomics profiling of 242 HCC tumor nodules and 58 adjacent nontumor tissues from 58 patients with multifocal HCC, revealing heterogeneous microbial communities in multifocal HCC. The presence of bacteria in HCC nodules was confirmed by Gram stain, lipopolysaccharide, lipoteichoic acid staining, and transmission electron microscopy. Mutational profiling stratified patients into intrahepatic metastasis (IM)-HCC and multicentric occurrence (MO)-HCC. Bacterial communities differed between IM and MO nodules (P = 0.01). A nine-bacterium biomarker panel could distinguish IM nodules from MO nodules with an AUROC of 0.795. The epithelial-mesenchymal transition pathway was upregulated in IM nodules and correlated with IM-enriched bacteria. IM-enriched bacteria such as Enterococcus faecalis and Streptococcus anginosus promoted HCC cell migration, invasion, and tumor progression in orthotopic HCC mouse models by inducing an immunosuppressive microenvironment and epithelial-mesenchymal transition. Collectively, the intrahepatic microbiome contributes to the heterogeneity and pathogenesis of multifocal HCC.
We reveal intraindividual heterogeneous microbial communities among nodules from patients with multifocal HCC. IM-HCC-enriched bacteria promote tumor growth and influence the tumor microenvironment of HCC. Our work highlights the necessity of considering bacterial heterogeneity as biomarkers and targets for multifocal HCC therapeutic intervention. See related commentary by Dzutsev and Trinchieri, p. 1540.
多灶性肝细胞癌（HCC）肝内微生物群的特征及其与基因组改变的关联仍不清楚。在本研究中，我们对58例多灶性HCC患者的242个HCC肿瘤结节和58个相邻非肿瘤组织进行了多组学分析，揭示了多灶性HCC中微生物群落的异质性。通过革兰氏染色、脂多糖、脂磷壁酸染色和透射电子显微镜证实了HCC结节中细菌的存在。突变分析将患者分为肝内转移（IM）-HCC和多中心发生（MO）-HCC。IM结节和MO结节中的细菌群落存在差异（P = 0.01）。一个由九种细菌组成的生物标志物组能够以0.795的曲线下面积（AUROC）区分IM结节和MO结节。上皮-间质转化途径在IM结节中上调，并与IM富集的细菌相关。粪肠球菌和咽峡炎链球菌等IM富集细菌通过诱导免疫抑制微环境和上皮-间质转化，促进原位HCC小鼠模型中的HCC细胞迁移、侵袭和肿瘤进展。总体而言，肝内微生物群促成了多灶性HCC的异质性和发病机制。
我们揭示了多灶性HCC患者结节间个体内的异质性微生物群落。IM-HCC富集的细菌促进肿瘤生长并影响HCC的肿瘤微环境。我们的工作强调了将细菌异质性视为多灶性HCC治疗干预的生物标志物和靶点的必要性。见Dzutsev和Trinchieri的相关评论，第1540页。
