Small extracellular vesicles convey the stress response of tumour cells

Abstract

Exosomes are small extracellular vesicles (sEVs), playing a crucial role in the intercellular communication in physiological as well as pathological processes. Here, we aimed to study whether the melanoma-derived seV-mediated communication could adapt to microenvironmental stresses. We compared B16F1 cell-derived sEVs released under normal and stress conditions, including cytostatic, heat and oxidative stress. The miRNome and proteome showed substantial differences across the sEV groups and bioinformatics analysis of the obtained data by the Ingenuity Pathway Analysis also revealed significant functional differences. The in silico predicted functional alterations of seVs were validated by in vitro assays. For instance, melanoma-derived sEVs elicited by oxidative stress increased Ki-67 expression of mesenchymal stem cells (MSCs); cytostatic stress-resulted sEVs facilitated melanoma cell migration; all sEV groups supported microtissue generation of MSC-B16F1 co-cultures in a 3D tumour matrix model. Based on this study, we concluded that (i) molecular patterns of tumourderived sEVs, dictated by the microenvironmental conditions, resulted in specific response patterns in the recipient cells; (ii) in silico analyses could be useful tools to predict different stress responses; (iii) alteration of the seV-mediated communication of tumour cells might be a therapy-induced host response, with a potential influence on treatment efficacy. Exosomes are small (30-200 nm) 1 endosome-derived vesicles that are actively secreted into the extracellular environment from most cell types. Initially, exosomes were proposed to eliminate cellular waste, but it has been proven that they also play a key role in the intercellular communication between adjacent as well as distal cells through the horizontal transfer of lipids, proteins and nucleic acids. Over the past three decades, exosomes have surged to the forefront of cell biology research, and recently an increasing body of evidence indicates that this exosomal communication is a deliberate and highly orchestrated process. Clinical relevance of exosomes is also considerable, since they are associated with numerous physiological and pathological conditions, including cancer diseases 2 .