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 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.