Poster Presentation 25th Lorne Cancer Conference 2013

PTRF/cavin-1 modulates exosome content and function (#215)

Kerry L Inder 1 , Lara Petelin 1 , Jayde Ruelcke 1 , Eunju Choi 1 , Antje Blumenthal 1 , Yaxuan Liang 2 , Lara Mehal 2 , Dietmar Hutmacher 3 , Robert G Parton 4 , Michelle M Hill 1
  1. University of Queenland Diamantina Institute, Woollongabba, QLD, Australia
  2. New York University, New York, Australia
  3. Institute for Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
  4. Institute for Molecular Bioscience, Brisbane, Australia

Recent studies have established a role for tumour-secreted exosomes in cancer development and progression. Exosomes are enriched in cholesterol and sphingolipids, and our recent work revealed a concomitant alteration of lipid raft and exosome proteomes from prostate cancer PC3 cells, when caveolae formation was induced by the co-factor PTRF/cavin-1. We previously confirmed that cavin-1 expression altered exosomal but not cellular content suggesting modulation of trafficking pathways. Here we investigated the effect of cavin-1 expression on the function of PC3 exosomes. Electron microscopy showed that exosome morphology was not altered by cavin-1. Quantitation of exosome size using dynamic light scattering revealed a significant reduction in the mean exosome diameter and number of exosomes released per cell for cavin-1 cells compared to control cells. To investigate the biological significance of the change in exosome content we examined the exosome function in vitro using 3 cell models: osteoclast differentiation, osteoblast proliferation and macrophage polarisation. Exosomes from PC3 cells induced differentiation of RAW264.7 cells to osteoclast-like multi-nucleate, TRAP-expressing cells, and stimulated human primary osteoblast proliferation compared to control. In the same assays, exosomes derived from cavin-1 PC3 cells failed to induce multinucleate osteoclasts and had reduced ability to stimulate osteoblast proliferation. In contrast, exosomes from control and cavin-1 cells had no effect on differentiation of monocytes into macrophages. These results demonstrate selective biological function for PC3-derived exosomes. Using fluorescently-labelled exosomes we demonstrated reduced uptake to target cells of cavin-1 derived exosomes compared to control. Proteinase K and neuraminidase treatment to remove exosomal surface protein and sialic acid, modulated exosome uptake into RAW264.7 cells. In summary, our data show that cavin-1 modulates the number, size, content and function of PC3 exosomes. Taken together with our previous report, we suggest modulation of lipid raft content and dynamics as the molecular mechanism.