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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.

SUBMITTER: Tang WC

PROVIDER: S-EPMC10108171 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Tang Wing Chung WC Tsao Sai Wah SW Jones Gareth E GE Liu Xiong X Tsai Ming Han MH Delecluse Henri-Jacques HJ Dai Wei W You Chanping C Zhang Jun J Huang Shaina Chor Mei SCM Leung Manton Man-Hon MM Liu Tengfei T Ching Yick Pang YP Chen Honglin H Lo Kwok Wai KW Li Xin X Tsang Chi Man CM

The Journal of pathology 20230106 2

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 mobil ...[more]

PMID: 36420735

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Project description:Background Mesenchymal stem/stromal cells (MSCs) acquire immunosuppressive capacity only in an inflammatory microenvironment. This can be recapitulated in vitro by treating MSCs with inflammatory cytokines TNFα and IFNγ, which induce indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene-6 (TSG-6). However, the signaling pathways downstream of the cytokines remain to be elucidated. Methods Inflammatory bowel disease (IBD) mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. Human UC-MSCs were pretreated with TNF-α and IFN-γ for 24 h and were then infused intravenously at day 2 of DSS administration. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay. Real-time PCR and Western blot were used to examine the mRNA level and protein expression. MSCs overexpressing constitutive active AKT or dominant negative AKT were generated and were analyzed. The glycolysis level of the MSCs was measured using Extracellular Flux Analyzer. 2-NBDG was used to monitor the uptake of glucose by MSCs. Results TNFα and IFNγ treatment led to rapid consumption of glucose and metabolic skewing toward glycolysis in MSCs, which was required for the therapeutic efficacy of MSCs on IBD. Blockade of glycolysis in MSCs inhibited the expression of immunomodulatory molecules, IDO and TSG-6, as well as the therapeutic effect on IBD. Moreover, PI3K-AKT signaling axis was rapidly activated and was required for the skewing toward glycolysis induced by TNFα and IFNγ. MSCs expressing dominant negative AKT were compromised in their therapeutic efficacy on IBD. Conclusion The glycolysis-dependent anti-inflammatory property of MSCs conferred by inflammatory cytokines is mediated by PI3K-AKT signaling pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03178-3.

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

Publications

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

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