2013 San Antonio Breast Cancer Symposium (SABCS)

Preventing metastases by tackling exosomes

Dr Jeff Wrana - University of Toronto, Canada

http://ecancer.org/conference/435-2013-san-antonio-breast-cancer-symposium--sabcs/video/2587/preventing-metastases-by-tackling-exosomes.php

The traditional model for the way cells communicate has been diffusible proteins that can obviously transmit information between cells. Exosomes were identified, characterised, decades ago as small vesicles, membrane-bound vesicles, that are produced by cells and it’s now becoming more and more clear that these exosomes can carry large amounts of information as a means of communicating between cells.

In our studies we’re interested in how cancer cells become motile, move around, and potentially that’s obviously linked to the process of metastasis. In the course of these studies we got interested in understanding how signals from fibroblasts that are surrounding tumour cells are actually stimulating the motility of those tumour cells. What we discovered is that a main carrier of that information is exosomes themselves. The surprise in the study was not that the exosomes were just carrying a signal that was stimulating the cell to move and metastasise but what they were actually doing is mobilising an intrinsic cell signalling pathway in the tumour cell that was then stimulating the cell to move. This correlated also with metastasis in an animal model.

What we found is that the signalling pathway that’s stimulating the cells to move is what’s called planar cell polarity signalling. Planar cell polarity signalling was first described in Drosophila, the fruit fly, and it was really conceptualised as a tissue polarity thing. So it’s the kind of thing that organises the way the hair on your head is arranged. So, for instance, if you had defects in planar cell polarity, your hair would be dishevelled and it wouldn’t really have waves in it the way that it does. So planar cell polarity is really important for organising tissue and the interesting part of our studies was that we found that this planar cell polarity pathway is also manifested in single motile cells. What it does is actually controlling the activity or the protrusive activity of these tumour cells.

How do you think this will relate to inhibiting metastasis?

What we found is that if you interfere with this planar cell polarity pathway you actually can completely shut down cell motility and it actually, in an animal model, blocks metastasis quite potently. So we think if we can interfere with this particular pathway this would be a novel pathway for studying cell motility and that that’s a potential for interfering with metastasis. In our studies the data showed quite clearly that this was really a pathway selected for metastasis and not just a pathway that was affecting, say, overall tumour growth.

Can you see this moving into the clinic in the next ten years?

I’d like to but I don’t want to promise anything. But, yes, I think it’s too early to tell because this pathway is very novel so identifying potential targetable components of this pathway is still in its early infancy. Part of the work I’ll talk about here at the conference is discovery of an enzyme that lies downstream of one of the proteins in this pathway and that if you block that enzyme, which is obviously much more tractable to drug development, you also can completely interfere with breast cancer cell motility induced by this exosome mediated pathway.