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

TY - JOUR

T1 - Latent membrane protein 1 and macrophage-derived TNFα synergistically activate and mobilize invadopodia to drive invasion of nasopharyngeal carcinoma

AU - Tang, Wing Chung

AU - Tsao, Sai Wah

AU - Jones, Gareth E.

AU - Liu, Xiong

AU - Tsai, Ming Han

AU - Delecluse, Henri Jacques

AU - Dai, Wei

AU - You, Chanping

AU - Zhang, Jun

AU - Huang, Shaina Chor Mei

AU - Leung, Manton Man hon

AU - Liu, Tengfei

AU - Ching, Yick Pang

AU - Chen, Honglin

AU - Lo, Kwok Wai

AU - Li, Xin

AU - Tsang, Chi Man

N1 - Funding Information: CMT was funded by the General Research Fund (GRF): 14113620; Early Career Scheme (ECS) 24114922; the Health and Medical Research Fund (HMRF): 09203176; Faculty Innovation Award (FIA2020/A/01); and Areas of Excellence Scheme (AoE): AoE/M401/20. SWT was funded by GRF: 17122420 and 17114818; HMRF: 04151726; and the Collaborative Research Fund (CRF): C7027‐16G and C1013‐15G. XL and SWT were co‐funded by the NSFC/RGC Joint Research Project: N_HKU735/18 and 81861168033. KWL was funded by the Innovation and Technology Fund (ITF): MRP/036/21X; GRF: 14101721; HMRF: 08191046; and CRF: C4001‐18GF. Funding Information: We are most grateful to Scott A Weed (West Virginia University, USA) for providing pS405 and pS418 cortactin antibodies; Jaap M Middeldorp for providing the LMP1 antibody (Amsterdam University Medical Center, The Netherlands); and the Imaging and Flow Cytometry Core, Centre for PanorOmic Sciences, HKU, for their assistance with imaging and flow cytometry (The University of Hong Kong, HK). CMT was funded by the General Research Fund (GRF): 14113620; Early Career Scheme (ECS) 24114922; the Health and Medical Research Fund (HMRF): 09203176; Faculty Innovation Award (FIA2020/A/01); and Areas of Excellence Scheme (AoE): AoE/M401/20. SWT was funded by GRF: 17122420 and 17114818; HMRF: 04151726; and the Collaborative Research Fund (CRF): C7027-16G and C1013-15G. XL and SWT were co-funded by the NSFC/RGC Joint Research Project: N_HKU735/18 and 81861168033. KWL was funded by the Innovation and Technology Fund (ITF): MRP/036/21X; GRF: 14101721; HMRF: 08191046; and CRF: C4001-18GF. Publisher Copyright: © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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.

KW - Epstein–Barr virus infection

KW - invadopodia

KW - invasion

KW - latent membrane protein 1

KW - live-cell imaging

KW - nasopharyngeal carcinoma

KW - tumor-associated macrophage

UR - http://www.scopus.com/inward/record.url?scp=85145720378&partnerID=8YFLogxK

U2 - 10.1002/path.6036

DO - 10.1002/path.6036

M3 - Article

C2 - 36420735

AN - SCOPUS:85145720378

SN - 0022-3417

VL - 259

SP - 163

EP - 179

JO - Journal of pathology

JF - Journal of pathology

IS - 2

ER -