HHLA2 activates c-Met and identifies patients for targeted therapy in hepatocellular carcinoma

作者：Xubo Huang, Runya Fang, Yuqian Pang, Zhe Zhang, Jieru Huang, Yuting Li, Tao Yuan, Yun Zeng, Zhao Yao, Silvia Vega-Rubín-de-Celis, Josephine Thinwa, Qisheng Zhang, Hao Shen, Jiahong Wang, Feng Shen, Yongjie Wei · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03407-6 · 被引用次数：3 · 研究领域：Liver physiology and pathology、Cancer Cells and Metastasis、Inflammatory mediators and NSAID effects

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options in advanced stages. While c-Met is a promising therapeutic target in HCC, identifying patients who will benefit from c-Met inhibitors remains a significant challenge. This study aimed to investigate the role of HHLA2, a B7 family member, in HCC and its potential as a liquid biopsy marker for c-Met inhibitor therapy. METHODS: HHLA2 expression was analyzed in clinical HCC samples and public databases. In vitro studies using HCC cell lines assessed HHLA2's impact on proliferation, migration, invasion, and angiogenesis. In vivo studies using mouse models (orthotopic xenografts and hydrodynamic tail vein injection) evaluated HHLA2's role in tumor growth and metastasis. Mass spectrometry, co-immunoprecipitation, split-luciferase, and ELISA assays were used to investigate HHLA2-c-Met interactions. Patient-derived organoids (PDOs) were used to assess drug response. Statistical analyses included Student's t-tests, ANOVA, and Cox regression. RESULTS: HHLA2 was found to be upregulated in HCC and associated with advanced disease, aggressive clinicopathological features, and poor prognosis. HHLA2 interacted with and constitutively activated c-Met, leading to increased expression of MMP9 and VEGFA, enhancing HCC cell proliferation, invasion, and angiogenesis. HHLA2 also suppressed hepatic natural killer cell infiltration in vivo. Inhibition of c-Met with PHA665752 effectively reverse...