Metabolic expression profiling analysis reveals pyruvate-mediated EPHB2 upregulation promotes lymphatic metastasis in head and neck squamous cell carcinomas

Lymphatic metastasis is a well-known factor for head and neck squamous cell carcinoma (HNSCC) that initiates distant metastasis, which caused major death in most patients with cancer. 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 and identified that an enriched carbohydrate metabolism subgroup that was significantly associated with a high risk of lymphatic metastasis and worse clinical outcome. Moreover, we found that highly activated pyruvate metabolism, a central node in carbohydrate metabolism, endowed tumors with EPHB2 upregulation and promoted lymphatic metastasis independently of VEGF-C/VEGFR3 signaling pathway. Mechanically, high levels of nuclear acetyl-CoA from pyruvate metabolism promoted histone acetylation, which in turn transcriptionally upregulated EPHB2 expression in tumor cells. EPHB2 bound with EFNB1 in lymphatic endothelial cells to alleviate YAP/TAZ-mediated PROX1 transcriptional inhibition, which eventually promoted tumor lymphangiogenesis. Importantly, combined treatment with EFNB1-Fc and VEGFR3 inhibitor synergistic abrogated lymphangiogenesis in vitro and in vivo. 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.