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

Abstract 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 TNFα 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 TNFα 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 TNFα‐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. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.