MTDH in macrophages promotes the vasculogenic mimicry via VEGFA-165/Flt-1 signaling pathway in head and neck squamous cell carcinoma.

Vasculogenic mimicry (VM) refers to vessel-like structures formed by aggressive tumor cells and is closely associated with cancer invasion and metastasis. Here, we investigated the effect of macrophage-derived MTDH on VM formation in head and neck squamous cell carcinoma (HNSCC) and its underlying mechanism. Macrophages with MTDH overexpression (Mac-MTDH) promoted cancer cell VM formation, migration, and invasion in vitro. Moreover, MTDH overexpression triggered macrophage polarization into M2 type tumor-associated macrophages. Analysis of HNSCC clinical samples revealed that MTDH+ macrophages were predominantly located in the tumor-stromal region in proximity to VM and correlated with lymph node metastasis. Mechanistically, Mac-MTDH enhanced the expression and secretion of VEGFA-165 rather than other VEGFA isoforms via ß-catenin. The VEGFA-165/Flt-1 axis was responsible for Mac-MTDH's effects in cancer cells through p-STAT3/Twist1/VE-cadherin pathway. Using mouse model, we further confirmed that Mac-MTDH increased VM formation and cancer metastasis in vivo. Furthermore, in subcutaneous xenograft mouse model, HN6 + Mac-MTDH tumor exhibited elevated expression of p-STAT3 and Twist1 than HN6 + Mac-NC tumors. This study revealed that Mac-MTDH promoted VM formation, cancer cell migration and invasion, and cancer metastasis through VEGFA-165/Flt-1 axis, and that macrophage-derived MTDH could be a potential therapeutic target in HNSCC.