Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings.
Bibliographical noteFunding Information:
The authors would like to thank the members of the Tumor Microenvironment Laboratory of QIMR Berghofer Medical Research Institute for critical input and proofreading of the manuscript. We thank Sophie Krumeich for technical assistance, and Sarah Ellis from the Peter MacCallum Cancer Center, Melbourne, Australia for assistance with obtaining electron microscopy images. This work was funded by a grant from the National Breast Cancer Foundation Australia (IIRS-18-159) to A.M. and B.S.P.
© 2021, The Author(s).
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry,Genetics and Molecular Biology
- General Physics and Astronomy