LOXL2-enriched small extracellular vesicles mediate hypoxia-induced premetastatic niche and indicates poor outcome of head and neck cancer

• Published in: Theranostics Vol. 11; no. 19; pp. 9198 - 9216
• Main Authors: Zhu, Guiquan, Wang, Linlin, Meng, Wanrong, Lu, Shun, Cao, Bangrong, Liang, Xinhua, He, Chuanshi, Hao, Yaying, Du, Xueyu, Wang, Xiaoyi, Li, Longjiang, Li, Ling
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2021; Ivyspring International Publisher
• Subjects: Adult; Aged; Aged, 80 and over; Amino Acid Oxidoreductases - genetics; Amino Acid Oxidoreductases - metabolism; Angiogenesis; Animals; Cancer therapies; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell culture; Cell Line, Tumor; Cell Proliferation - genetics; Chemotherapy; China; Cloning; Epithelial-Mesenchymal Transition - genetics; Extracellular vesicles; Extracellular Vesicles - metabolism; Female; Gene expression; Gene Expression - genetics; Gene Expression Regulation, Neoplastic - genetics; Head & neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; Hypoxia; Male; Metabolism; Metabolites; Metastasis; Mice; Mice, Nude; Microscopy; Middle Aged; Neoplasm Invasiveness - genetics; Neoplasm Metastasis - physiopathology; Penicillin; Radiation; Research Paper; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - pathology; Transcriptome - genetics; Tumor Hypoxia - physiology; Tumor Microenvironment - physiology; Xenograft Model Antitumor Assays; China; United States > US; small extracellular vesicle; hypoxia; premetastatic niche; Lysyl Oxidase Like 2; head and neck squamous cell carcinoma
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/THNO.62455

Small extracellular vesicles (sEVs) operate as a signaling platform due to their ability to carry functional molecular cargos. However, the role of sEVs in hypoxic tumor microenvironment-mediated premetastatic niche formation remains poorly understood. : Protein expression profile of sEVs derived from normoxic and hypoxic head and neck squamous cell carcinoma (HNSCC) cells were determined by Isobaric Tagging Technology for Relative Quantitation. In vitro invasion assay and in vivo colonization were performed to evaluate the role of sEV-delivering proteins. : We identified lysyl oxidase like 2 (LOXL2) which had the highest fold increase in hypoxic sEVs compared with normoxic sEVs. Hypoxic cell-derived sEVs delivered high amounts of LOXL2 to non-hypoxic HNSCC cells to elicit epithelial-to-mesenchymal transition (EMT) and induce the invasion of the recipient cancer cells. Moreover, LOXL2-enriched sEVs were incorporated by distant fibroblasts and activate FAK/Src signaling in recipient fibroblasts. Increased production of fibronectin mediated by FAK/Src signaling recruited myeloid-derived suppressor cells to form a premetastatic niche. Serum sEV LOXL2 can reflect a hypoxic and aggressive tumor type and can serve as an alternative to tissue LOXL2 as an independent prognostic factor of overall survival for patients with HNSCC. : sEVs derived from the hypoxic tumor microenvironment of HNSCC can drive local invasion of non-hypoxic HNSCC cells and stimulate premetastatic niche formation by delivering LOXL2 to non-hypoxic HNSCC cells and fibroblasts to induce EMT and fibronectin production, respectively.