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Integrin α6-containing extracellular vesicles promote lymphatic remodelling for pre-metastatic niche formation in lymph nodes via interplay with CD151.
- Source :
-
Journal of extracellular vesicles [J Extracell Vesicles] 2024 Oct; Vol. 13 (10), pp. e12518. - Publication Year :
- 2024
-
Abstract
- Heterogeneous extracellular vesicles (EVs) from various types of tumours are acknowledged for inducing the formation of pre-metastatic "niches" in draining lymph nodes (LNs) to promote lymphatic metastasis. In order to identify the specific subpopulations of EVs involved, we performed high-resolution proteomic analysis combined with nanoflow cytometry of bladder cancer (BCa) tissue-derived EVs to identify a novel subset of tumour-derived EVs that contain integrin α6 (ITGA6 <superscript>+</superscript> EVs) and revealed the positive correlation of ITGA6 <superscript>+</superscript> EVs with the formation of pre-metastatic niche in draining LNs and lymphatic metastasis in multicentre clinical analysis of 820-case BCa patients. BCa-derived ITGA6 <superscript>+</superscript> EVs induced E-selectin (SELE)-marked lymphatic remodelling pre-metastatic niche and promoted metastasis in draining LNs through delivering cargo circRNA-LIPAR to lymphatic endothelial cells in vivo and in vitro. Mechanistically, LIPAR linked ITGA6 to the switch II domain of RAB5A and sustained RAB5A GTP-bound activated state, thus maintaining the production of ITGA6 <superscript>+</superscript> EVs loaded with LIPAR through endosomal trafficking. ITGA6 <superscript>+</superscript> EVs targeted lymphatic vessels through ITGA6-CD151 interplay and released LIPAR to induce SELE overexpression-marked lymphatic remodelling pre-metastatic niche. Importantly, we constructed engineered-ITGA6 EVs to inhibit lymphatic pre-metastatic niche, which suppressed lymphatic metastasis and prolonged survival in preclinical models. Collectively, our study uncovers the mechanism of BCa-derived ITGA6 <superscript>+</superscript> EVs mediating pre-metastatic niche and provides an engineered-EV-based strategy against BCa lymphatic metastasis.<br /> (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)
- Subjects :
- Humans
Animals
Mice
Cell Line, Tumor
Female
Male
Lymphangiogenesis
Endothelial Cells metabolism
E-Selectin metabolism
Extracellular Vesicles metabolism
Integrin alpha6 metabolism
Tetraspanin 24 metabolism
Lymph Nodes metabolism
Lymph Nodes pathology
Lymphatic Metastasis
Urinary Bladder Neoplasms pathology
Urinary Bladder Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2001-3078
- Volume :
- 13
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of extracellular vesicles
- Publication Type :
- Academic Journal
- Accession number :
- 39329462
- Full Text :
- https://doi.org/10.1002/jev2.12518