Miao Jingjing, Chen Boyu, Zhang Lu, Lu Zhongming, Wang Rui, Wang Chunyang, Jiang Xingyu, Shen Qi, Li Yue, Shi Dongni, Ouyang Ying, Chen Xiangfu, Deng Xiaowu, Zhang Siyi, Zou Hequn, Chen Shuwei
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
J Transl Med. 2025 Mar 12;23(1):316. doi: 10.1186/s12967-025-06305-9.
Lymphatic metastasis is a well-known factor for initiating distant metastasis of head and neck squamous cell carcinoma (HNSCC), which caused major death in most patients with cancer. Meanwhile, metabolic reprogramming to support metastasis is regarded as a prominent hallmark of cancers. However, how metabolic disorders drive in HNSCC remains unclear. We firstly established a new classification of HNSCC patients based on metabolism gene expression profiles from the TCGA and GEO database, and identified an enriched carbohydrate metabolism subgroup which was significantly associated with lymphatic metastasis and worse clinical outcome. Moreover, we found that highly activated pyruvate metabolism endowed tumors with EPHB2 upregulation and promoted tumor lymphangiogenesis independently of VEGF-C/VEGFR3 signaling pathway. Mechanically, high nuclear acetyl-CoA production from pyruvate metabolism promoted histone acetylation, which in turn transcriptionally upregulated EPHB2 expression and secretion in tumor cells. EPHB2 bound with EFNB1 in lymphatic endothelial cells promoted YAP/TAZ cytoplasmic retention, which alleviated YAP/TAZ-mediated prospero homeobox protein 1 (PROX1) transcriptional repression, and then triggered tumor lymphangiogenesis. Importantly, combined treatment with EFNB1-Fc and VEGFR3 inhibitor synergistic abrogated lymphangiogenesis in vitro and in vivo, suggesting that targeting EPHB2 might be a potential strategy to patients with no or slight response to VEGFR3 inhibitor. These findings uncover the mechanism by which pyruvate metabolism is linked to lymphatic metastasis of tumor and provides a promising therapeutic strategy for the prevention of HNSCC metastasis.
淋巴转移是头颈部鳞状细胞癌（HNSCC）发生远处转移的一个众所周知的因素，它导致大多数癌症患者死亡。同时，支持转移的代谢重编程被视为癌症的一个显著特征。然而，代谢紊乱如何在HNSCC中发挥作用仍不清楚。我们首先基于来自TCGA和GEO数据库的代谢基因表达谱建立了一种新的HNSCC患者分类方法，并确定了一个富集的碳水化合物代谢亚组，该亚组与淋巴转移和较差的临床结果显著相关。此外，我们发现高度激活的丙酮酸代谢使肿瘤细胞EPHB2上调，并独立于VEGF-C/VEGFR3信号通路促进肿瘤淋巴管生成。机制上，丙酮酸代谢产生的高核乙酰辅酶A促进组蛋白乙酰化，进而转录上调肿瘤细胞中EPHB2的表达和分泌。EPHB2与淋巴管内皮细胞中的EFNB1结合，促进YAP/TAZ在细胞质中的滞留，减轻YAP/TAZ介导的prospero同源盒蛋白1（PROX1）的转录抑制，进而引发肿瘤淋巴管生成。重要的是，EFNB1-Fc和VEGFR3抑制剂联合治疗在体外和体内协同消除了淋巴管生成，这表明靶向EPHB2可能是对VEGFR3抑制剂无反应或反应轻微的患者的一种潜在治疗策略。这些发现揭示了丙酮酸代谢与肿瘤淋巴转移相关的机制，并为预防HNSCC转移提供了一种有前景的治疗策略。
