Latent membrane protein 1 and macrophage-derived TNFα synergistically activate and mobilize invadopodia to drive invasion of nasopharyngeal carcinoma

作者：Tang, Wing Chung; Tsao, Sai Wah; Jones, Gareth E.; Liu, Xiong; Tsai, Ming Han; Delecluse, Henri-Jacques; Dai, Wei; You, Chanping; Zhang, Jun; Huang, Shaina Chor Mei; Leung, Manton Man-hon; Liu, Tengfei; Ching, Yick Pang; Chen, Honglin; Lo, Kwok Wai; Li, Xin^*; Tsang, Chi Man^*

来源：Journal of Pathology, 2023, 259(2): 163-179.

DOI：10.1002/path.6036

• Epstein-Barr virus infection
• nasopharyngeal carcinoma
• invadopodia
• tumor-associated macrophage
• latent membrane protein 1
• invasion
• live-cell imaging

Invadopodia are actin-rich membrane protrusions that digest the matrix barrier during cancer metastasis. Since the discovery of invadopodia, they have been visualized as localized and dot-like structures in different types of cancer cells on top of a 2D matrix. In this investigation of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), a highly invasive cancer frequently accompanied by neck lymph node and distal organ metastases, we revealed a new form of invadopodium with mobilizing features. Integration of live-cell imaging and molecular assays revealed the interaction of macrophage-released TNF alpha and EBV-encoded latent membrane protein 1 (LMP1) in co-activating the EGFR/Src/ERK/cortactin and Cdc42/N-WASP signaling axes for mobilizing the invadopodia with lateral movements. This phenomenon endows the invadopodia with massive degradative power, visualized as a shift of focal dot-like digestion patterns on a 2D gelatin to a dendrite-like digestion pattern. Notably, single stimulation of either LMP1 or TNF alpha could only enhance the number of ordinary dot-like invadopodia, suggesting that the EBV infection sensitizes the NPC cells to form mobilizing invadopodia when encountering a TNF alpha-rich tumor microenvironment. This study unveils the interplay of EBV and stromal components in driving the invasive potential of NPC via unleashing the propulsion of invadopodia in overcoming matrix hurdles.

• 单位
  南方医科大学