Oral Presentation Australasian Extracellular Vesicles Conference 2020

Tumor microenvironmental cytokines bound to cancer-derived exosomes guide metastatic dissemination (#11)

Luize G Lima 1 , Sunyoung Ham 1 2 , Hyunku Shin 3 , Chai Pei Zhi Edna 1 4 , Erica SH Lek 1 5 , Richard J Lobb 1 , Alexandra F Müller 1 , Suresh Mathivanan 6 , Belinda Yeo 7 , Yeonho Choi 3 8 9 , Belinda S Parker 6 , Andreas Möller 1 2 4
  1. QIMR Berghofer, Herston, QLD, Australia
  2. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
  3. Department of Bio-convergence Engineering, Korea University, Seoul, South Korea
  4. Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
  5. School of Chemistry and Molecular Biosciences, Faculty of Science, University of Queensland, Brisbane, QLD, Australia
  6. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
  7. Olivia Newton-John Cancer Research Institute, Austin Hospital, Heidelberg, Victoria, Australia
  8. School of Biomedical Engineering, Korea University, Seoul, South Korea
  9. Department of Bioengineering, Korea University, Seoul, South Korea

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 their integrin 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 cytokines present in the tumor microenvironment decorate cancer exosomes via binding to surface proteoglycans, causing exosome accumulation into specific cell lineages and distal organs. Cytokine-mediated exosome retention results in pre-metastatic niche formation within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are mainly directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a novel and crucial determinant of exosome-cell interactions. Our results add a tumor microenvironmental aspect to the cancer cell-intrinsic mechanisms of organotropism identified thus far and will ultimately provide novel diagnostic and therapeutic tools to reduce the mortality associated with cancer metastasis.The fact that exosomes isolated from the blood of healthy subjects are also cytokine-conjugated, albeit displaying a different profile from exosomes isolated from cancer patients, further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings.