Inhibition of alpha v beta 3 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles

Author(s)

Altei, Wanessa F. ; Pachane, Bianca C. ; dos Santos, Patty K. ; Ribeiro, Ligia N. M. ; Sung, Bong Hwan ; Weaver, Alissa M. ; Selistre-de-Araujo, Heloisa S.

• Document type: Journal article
• Source: CELL COMMUNICATION AND SIGNALING; v. 18, n. 1, p. 15-pg., 2020-09-25.

Abstract

Background; Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells. Methods: To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for alpha v beta 3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments. Results: We find that SEVs secreted from MDA-MB-231 breast cancer cells carry alpha v beta 3 integrin and bind directly to fibronectin-coated plates, which is inhibited by DisBa-01. SEV coating on tissue culture plates also induces adhesion of MDA-MB-231 cells, which is inhibited by DisBa-01 treatment. Analysis of EV uptake and interchange between cells reveals that the amount of CD63-positive EVs delivered from malignant MDA-MB-231 breast cells to non-malignant MCF10A breast epithelial cells is reduced by DisBa-01 treatment. Inhibition of alpha v beta 3 integrin decreases CD63 expression in cancer cells suggesting an effect on SEV content. Conclusion: In summary, our findings demonstrate for the first time a key role of alpha v beta 3 integrin in cell-cell communication through SEVs. (AU)

• FAPESP's process: 14/18747-8 - Tumor breast cell exosomes and their role in cell adhesion during metastasis
• Grantee: Wanessa Fernanda Altei
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/00798-2 - The extracellular matrix in aging, exercise and in the tumor microenvironment
• Grantee: Heloisa Sobreiro Selistre de Araújo
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/22539-7 - The role of integrins on exosome binding to the extracellular matrix and its contribution to tumor progression
• Grantee: Wanessa Fernanda Altei
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor