Fusobacterium nucleatum promotes tumor extravasation and metastasis in head and neck cancer via TLR4/MYB/ESPN axis

Abstract Patients with metastasis have an extremely poor prognosis in head and neck squamous cell carcinoma (HNSCC). Emerging studies have illuminated the impact of intratumor microbiota on cancer metastasis, though the specific role of Fusobacterium nucleatum ( F. nucleatum ) in HNSCC metastasis remains unresolved. This research found that intratumoral F. nucleatum abundance was elevated and correlated to diminished disease-free survival in HNSCC patients exhibiting lymph node metastasis. F. nucleatum invasion into primary and metastatic tumor tissues was observed using fluorescence in situ hybridization . F. nucleatum induced adhesion to endothelial cells and facilitated transendothelial migration via upregulating ESPN expression in HNSCC cells, which is an actin-binding protein. Mechanistically, F. nucleatum activated TLR4 signaling, inducing elevated expression of the transcription factor MYB, which subsequently stimulated ESPN transcription. Furthermore, metronidazole treatment significantly reduced metastatic incidence in vivo. These results indicate the significant potential of targeting F. nucleatum as a therapeutic approach in metastatic HNSCC.