Collaborative work from DPAG and Oncology researchers has revealed a potential new pathway to block the production of a specific group of exosomes made in the cell’s recycling system that can promote the growth of cancerous tumours.
Rab11a-exosomes are produced by human cells, and equivalent exosomes are made within normal prostate-like secondary cells in fruit flies, where they appear in confocal images as yellow dots, inside large Rab11-positive secretory compartments (left image). Blocking expression of an accessory ESCRT-III suppresses this exosome formation (right image), but not other exosome production in both flies and human cancer cells. Secondary cells are outlined by white dashed lines and examples of ‘Normal’ and ‘Blocked’ Rab11 compartments are marked by white arrows.
Exosomes are nano-sized extracellular vesicles formed inside all the body’s cells within membrane-bound compartments and released when these compartments fuse with the plasma membrane. Their multimolecular cargos, containing mixtures of proteins, RNAs and other molecules, allow them to send complex messages to reprogramme target cells. While exosomes play important roles in healthy physiological processes such as immunity and reproduction, they also drive disease processes, such as cancer progression and metastasis.
Associate Professor Deborah Goberdhan’s group, alongside Professor Adrian Harris in the Department of Oncology as part of their ongoing work on human exosome function, has collaborated with Professor Clive Wilson’s team to undertake complementary experiments with a cell model of exosome biology in fruit flies. Previously, the collaborative team of researchers identified a specific set of exosomes, Rab11a-exosomes, made in compartments called recycling endosomes. These Rab11a-exosomes carry a different set of cargos that help cancers to grow and become resistant to commonly used treatments.
In newly published research, the team has now identified a way to selectively block the production of Rab11a-exosomes. They have also shown that these vesicles play critical roles in fly reproduction and in the signalling associated with human cancer progression, despite the fact that they only constitute a small proportion of all vesicles released by tumour cells.
Associate Professor Goberdhan said: “Most functional studies of exosomes have to rely on complex mixtures of secreted vesicles and can’t distinguish the origin of the exosomes with the key biological activities. Our work overcomes these problems and provides a powerful new tool that will be useful in developing biomarkers for exosome-associated diseases like cancer, as well as new therapeutics.”
Professor Clive Wilson added: “Working with fly and human cells has given us a unique advantage in addressing this problem. We’ve been able to rapidly test ideas generated from work in human cells, using flies, then take those findings to identify mechanisms specific for Rab11a-exosomes in cancer cells.”
The collaborative team is now studying additional druggable mechanisms that control Rab11a-exosome formation and the relevance of this signalling to other diseases.