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 tumour-derived 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.
Bibliographical noteFunding Information:
The authors thank for any help of other researchers in the Biological Research Centre of the Hungarian Academy of Sciences, namely Lilla Pinter, Ede Migh and Arpad Balind for their technical assistance, Ferenc Kovacs, Andras Kriston, Norbert Bara for developing the SCT Analyzer 1.0, Zsolt Szegletes for the AFM images, Andras Kincses for the DLS measurements of sEVs, Maria Deli for providing the bEnd.3 cell line and members of the Laboratory of Tumor Immunology and Pharmacology for making available their tissue culture facility. We would like to thank Zoltan Arpad Varadi for the IT support. This work was supported by GINOP-2.3.2-15-2016-00015; GINOP-2.2.1-15-2017-00052 and NKFI-6-K funding scheme (11493 project). The Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT and the University of Szeged Open Access Fund is also acknowledged. Krisztina Buzas and Tibor Pankotai are supported by János Bolyai Research Scholarship of the Hungarian Academy of Sciences, Krisztina Buzas is also supported by the ÚNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology.
© 2019, The Author(s).