Monday, May 20, 2013

Metastasis - an overview and network perspective

My collaborators, +Philip Gerlee +David Basanta and +Alexander Anderson and I have been working on the problem of metastasis for a few years now, using a physical sciences, network based perspective to try to uncover some truths about this enigmatic process.

Metastatic disease has always been an interest of mine clinically for a number of reasons.  First, metastatic disease causes 90% of cancer death, and the vast majority of morbidity.  Second, for the most part (with a FEW counter examples like testicular cancer and some subsets of limited metastatic disease) we can't cure these patients.  Finally, radiation therapy - my specialty - is extremely well suited to help palliate patients with metastatic disease, and it is very gratifying to help patients in this way.

My scientific interest in metastasis started when I heard about the new technologies for measuring circulating tumor cells (CTCs). I realized that if we could have information about the concentration of these cells at different points in the vascular network at different times, we could infer quite a bit of information about what was happening to them in the organs: something that is currently really hard (impossible) to study in humans.  I drew a hand sketched drawing:

incomprehensible and ugly
and then worked with a medical illustrator in Peter Kuhn's lab named Katya Kadyshevskaya and we produced this: (moral of the story, work with a medical illustrator!)


beautiful and instructive

We published a version of this figure along with a short perspective piece in Nature Reviews Cancer - in which we posited that one could model the vascular system almost like an electrical circuit, considering the CTC flow like current, and the organs like resistors.  We then began working to use the formalism to learn something, other than to simply illustrate an idea (something that +Artem Kaznatcheev has recently talked about in his blog - see! we're learning from our models!)

What we first used this formalism to do was test the 'self-seeding' hypothesis of Larry Norton et al..  This is an hypothesis, first put into the literature in 2006 in Nature Medicine, which suggests that tumors can accelerate their growth by putting cells (CTCs) into the vasculature, letting them circulate around, and then come back to the primary.  This theoretical work was followed by a beautiful experimental paper in Cell, which showed that this phenomenon indeed was occurring, at least in mice. After lots of discussion, we couldn't agree about one of the conclusions of this work - that this mechanism (self-seeding from the primary directly back to itself) could truly drive primary tumor progression, so we built a model to test it.  You can see the full model in this pre-print on the arXiv, or, if you have access, in the Journal of the Royal Society Interface.  I also just presented a poster which summarizes both of the papers I just talked about, and put it on slideshare as an experiment:




Selfseedposter mss2013 from University of Oxford, Moffitt Cancer Center

In short, we find that it is far more likely that there is an intermediate step in between shedding and re-seeding where cells colonize a secondary tissue and subsequently shed their own progeny into the vasculature.  This adds a number of levels of complication and also opportunities for evolution in a foreign landscape - possibly speeding the 'search' for resistant phenotypes (a question I am eager to work on with +Steffen Schaper and +Daniel Nichol).

The next step we are working on (which should be on the arXiv soon) is to show that all metastatic patterns are able to be explained with this formalism, and further, that it represents a novel opportunity to personalized medicine - details to follow!

I've also just finished writing a short review of mathematical models of metastasis.  There has surprisingly little work done in this field and it represents a ripe area for theory.  This review should be available in a book published by Springer later this year, and you can read the pre-print on the arXiv here.  Springer is very open about the policy for pre-prints, which you can read here.  They basically say you can put up whatever you like, pre-acceptance/typesetting/copy editing, and they only reserve the rights to the version that they help with, which makes complete sense.  Seems this publisher is on board with #openaccess science.  Thank goodness.

I should also mention that my collaborator, +Philip Gerlee - wrote a nice post on metastasis a few days ago on his blog and he just promised me another post on it.  Keep your eyes peeled.