I see flowers & I think of metastasis: or how theoretical oncology has reshaped all of my thinking

I try to reserve weekends (or at least the hours of 8am to 8pm on the weekends) for time with my kids. I've got a little boy named Rhys, who is just now starting to learn language (he's about 18 months ago, really fun age) and a precocious little girl named Maren who is five and a half. I grew up either in a house full of books or out in the woods - my mom is a librarian and gardener and my dad is an English teacher, novelist and outdoorsman. Given this background, it is no wonder I still pay double most of my friend when I move because of the sheer weight of books my wife and I carry around, and also that I continue to love being outside.

My kids however, have a mom who was an occupational therapist and is now a photographer (gorgeous pics of our kids and other stuff on her page) and a dad who is a theoretical oncologist. So it shouldn't be surprising that my daughter doesn't mind a little gore, indeed she likes watching necropsies (thanks #thebrainscoop)

My daughter enthralled by a wolf necropsy! Science is awesome, thanks #thebrainscoop and @Ehmee ! #womeninstem pic.twitter.com/8U7w2AXy2f
— Jacob G Scott (@CancerConnector) December 6, 2013

a Tweet which actually ended up in an article about Dana Scully from the #xfiles, Emilie Graslie from #thebrainscoop and the girl from the #BigBangTheory which you can read here:

http://www.yesmagazine.org/happiness/less-big-bang-theory-more-dana-scully

and that we spend more time looking at Netter's anatomy book than almost anything else.  A few weeks ago, we busted out my microscope from medical school and I ordered a cool set of slides of amphibian and fish anatomy. She spent a few hours just fascinated and has subsequently asked to look at a ton of stuff under the scope (blue jay feathers are really fun - try it with the light from below, and then turn off the light and shine a light from above... great lesson on refraction).

That's her doing her best Ramon y Cajal impression on the left, and a tadpole stained (with H&E?) on the right. So, anyways, last weekend, we were trying to figure out what to do while her brother took a nap, and decided to see what we could see in the tanks of some of the bromeliads at the end of our street. We had watched a great David Attenborough documentary (oh yeah, they're pen pals)

Yeah, my daughter is a science nerd and #fangirl - first @Ehmee now David Attenborough! Good taste! pic.twitter.com/xowWctYymB
— Jacob G Scott (@CancerConnector) July 1, 2014

in which we learned that lots of micro-animals can live in bromeliad tanks.

Neither of us could have been happier, however, than when we saw this little beauty under the scope (or, I should say \mathcal{O}(100) of them)

I turned immediate to twitter to ask my friends what it was, and was immediately told it was an #ostracod, most likely Elpidia bromeliarium. I dug a little more into it and there is actually only one species of these described in Florida, and many new species are found all the time (most recently in the Honduran cloud forest - http://zookeys.pensoft.net/articles.php?id=3305 just last year!). So, needless to say we are pretty excited about the possibility of having found a new species.

What really got me going though, was the question of how these things get around?! There is only the one stand of bromeliads in my whole neighbourhood, and these little crustaceans can't move purposefully outside of even the tank they start in! Here is an early description of them I found from a journal in the 50s: http://journal.bsi.org/V06/4/

Then, on the same day, someone tweeted about a new computational study of 'jump dispersal' vs. 'rafting' a mechanisms for animals/plants to move over large distances (from island to island, say) and I started thinking about the problem of metastatic disease. When animals or plants 'raft' from one place to another (this is often called Oceanic dispersal as well), they are often swept from river banks with a hunk of vegetation or soil, and often more than one animal (especially for sexually reproducing creatures this is very important). I remember a PNAS paper in which the researchers (using a totally medieval experimental technique where they sewed two mice together - seriously) found that many successful metastases brought their own soil with them (in this case non-cancerous cells to support the metastatic seeds).

Taken from: http://blogs.scientificamerican.com/WSS/post.php?blog=33&post=939

There is more and more literature these days suggesting that it is clumps of circulating tumour cells that cause metastasis, not single cells (also a nice paper from my friend and collaborator, Peter Kuhn - lab page here). These clumps seem analogous to me to the rafts that other species might use, and could even be formed in the same way - in tumour associated mosaic vessels - there could certainly be a 'sweeping off' of a large clump of cells. If one disturbs the smoothness of a healthy vessel wall, there will be a disturbance in the otherwise (pretty close to) laminar flow and eddys will form and severely change the stress profile in the flowing fluid, creating a situation in which a chunk of cells could easily break free.

If true, this *sort of* obviates some of the modelling efforts that +Philip Gerlee and I (and others) have done considering the fate of single cells, but that work could certainly be reparameterised to consider the shedding rate of these clumps. My hypothesis would be that the results are quite similar, as the shedding rate would go down, but the chance of colonisation (given a clump landing somewhere) would be much higher.

Some other issues, like the Allee effect, could be overcome by this. Further, it offers some different ideas about therapeutics/preventatives. I wonder, for example, if there is any data on (non-liver) metastases in patients with Greenfield filters with colorectal cancer?

As for the little Elpidia - I found a cool study that shows, as +Benjamin Werner suggested, that they can survive in the guts of a number of creatures, so that's probably how they get around...

Anyways... ostracods, cancer, discuss.

n.b. there has been some interesting discussion on this thread already from a shorter post here:

https://plus.google.com/107832620883409249821/posts/UpC44CKSfyr

Memantine and WBRT

After the whole brain radiation review that my collaborators and I just published came out, my friend and colleague, Jack West, put a nice post up on his website Cancer Grace about it and asked a follow up question on twitter:

@CancerConnector Your review of WBRT for brain mets ( at http://t.co/Su9g4q3isf ) was terrific. What do you think of memantine's role now?
— H. Jack West, MD (@JackWestMD) May 5, 2013

He was referring to the recent Radiation Therapy Oncology Group's trial of memantine (a drug for dementia) given during whole brain radiation: RTOG0614.  So, to answer, I polled a couple of my friends who do nothing but neuro-oncology and reread the results of the trial (not out in published form yet, just as an abstract (paper #1 on this page) and the full talk from ASTRO).

As a quick summary: Whole brain radiation therapy (WBRT) is a treatment given to patients who have metastatic cancer in their brains.  There are a number of situations in which WBRT is given and it improves survival and significantly improves the life of patients.  On the downside, it has been shown to cause cognitive decline with as many as 60% of patients exhibiting measurable decline at 4 months after WBRT.  So, to combat this, a trial of memantine during and immediately after WBRT, an NMDA-receptor blocker used to treat Alzheimer's dementia was proposed and carried out.

In this trial, about 500 patients were enrolled, stratified by their RTOG brain metastasis RPA class (they only enrolled class 1 and 2 patients) and given either 20mg of memantine or placebo daily for 24 weeks.  A lot of their patients weren't able to be properly analyzed because of issues with survival (sadly, to be expected in this population), but those who were evaluable (~150) took a battery of 6 different cognitive tests.  The primary endpoint was performance on a specific test at the 24 week point, the e Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) and there was NOT a significant difference in the results of this (but it 'teetered on the edge of significance', with a p-value of 0.059).  Now, don't get me started on p-values.  Oops, too late.

The all holy p<0.05 is an arbitrary cutoff level by which we determine 'significance'.  I say again, arbitrary.  What it has become, I fear, is a gold-standard for a 'positive study'.  So in the case of this one, which technically did not meet its primary end point, many people are not swayed, because p wasn't less than or equal to 0.05.  the secondary endpoint, cognitive decline (a measure using several other of the tests) was met with p=0.01 and, crucially, there were no difference in side effects or survival. My *suspicion* is that the primary endpoint will be met if they can accrue (and analyze) another 50 patients, and this debate will end. However, until then, the jury is out.

Personally though, even though it failed to meet its primary end point, I will be recommending memantine to patients in a favorable RPA class getting WBRT, or at the very least having this discussion with my patient.

As an aside, the two Neuro specialists I polled had opposite answers, so it is fair to say that this remains in the undetermined category. But, the drug has been shown to be safe, and now *likely* efficacious. In a situation where we don't have other options, I'm sold.

My visit to the Mathematical Neuro-Oncology group at NorthWestern and the talk I gave about glioblastoma evolutionary dynamics and metastasis

I recently was honored by an invitation to visit Chicago and present some of my recent research to my friends and collaborators in a new group formed there by +Kristin Swanson called Mathematical Neuro-Oncology. I spent my time visiting their new, beautiful lab;

celebrating +Russ Rockne's transition;

having some coffee;

visiting my roots;

finding out that a paper long in the works, based on an opinion piece I wrote a few years ago about the effects of the #IDH1 mutation in secondary #glioblastoma, is finally in press at Neuro-Oncology (aside: Somehow there is an editorial written about it that is available (if you PAY, which I haven't yet), but the article is not yet itself available); listening to +Kristin Swanson practice for her +TEDx talk, which I've heard went well, but haven't seen yet (more info here: http://www.tedxuchicago.com/kristin-swanson); and actually giving a talk.

I couldn't decide what to talk about, and since the audience was going to be half computational neuro-oncologists (casual dress) and half general scientific/medical folks (white coast, ties, scrubs), I decided to give a talk in two parts - about a half an hour each.

I spent the first half hour talking about an exciting (to me at least) extension to previous work I've done here at IMO with +Alexander Anderson and +David Basanta and others on glioblastoma stem cells. I've blogged on this topic before, from posts about our recent paper in PLoS Comp Biology to a recent grant we submitted - which, frustratingly didn't get scored due to a very prototypical reviewer #3 (reviewers 1 and 2 gave us 1's 2's and 3's and reviewer #3 gave us 7's, 8's and 9's).

The second half I talked about the work I've done with +Philip Gerlee and +Alexander Anderson and others to understand how a filter-flow paradigm of metastatic spread can help us understand (and intervene) in the process of #metastasis itself. We've published most of this work as a perspective piece in Nature Reviews Cancer, a test of the self-seeding hypothesis in J. Roy. Soc. Interface, a review in a Springer textbook (pre-print here) and recently, a more clinically oriented piece under review at Clinical and Experimental Metastasis (you can see a pre-print here on the +bioRxiv Preprints site). Both I and Philip Gerlee have blogged about it (including a shared post here in response to a Cancer Research UK blog post which we took exception to (at least to parts of it)) in the past as well.

So - anyways, here are the slides. The first half is work in progress, and we're pretty excited about it. I'd love to know if anyone has any feedback.

Pint of Science, US

Wow - it's been a while since I wrote anything.  A combination of several academic visits from +Alex Fletcher and Anita Hjelmeland, trying desperately to make some headway on my thesis, and a teething toddler left this blogging effort at the bottom of the pile.  I've got a few posts I need to write to catch up, but I thought I'd start with this one.

Last year, a movement was started in the UK called pint of science who's stated mission is to bring top scientist into pubs to communicate their passion for science to everyman.  They began with 15 pubs in London, Oxford and Cambridge for a several days long festival to great acclaim.  The movement is now spreading, and my good friends +Parmvir Bahia, +David Basanta, +Arturo Araujo and new friend +Angela Rey decided to start the movement here in the US - aptly named, Pint of Science, US.  They have worked to find their own spin on the theme, and settled on holding both a live event, and also on a podcast, on a monthly basis.  The central theme is the same - communicate what it is that we do as scientists, and why we do it, to the folks with whom we live and work.

The first even was held two weeks ago today at the New World Brewery in Tampa, FL.  I was honored to be asked by my friends to be the first speaker.  This is both a good thing and a bad thing.  The expectations are low (or, undefined), but it is also a difficult ask, because there is no predetermined script to follow.  So, you'll notice some hems and hahs in my podcast.

PB doing the introduction...

The audience at this, the inaugural event, consisted entirely of friends and co-workers, so it felt a little strange telling my life story and trying to convince 'people' that mathematics can help to play a role in cancer research (as everyone knew my life story and DOES mathematical cancer research).  So, in some ways, this event was more difficult than any other event like this that I've done.  Strange to admit, but I was sweating bullets!

Anywho, after some gentle editing from the Pint of Science US team, a podcast emerged and the event was a success.  I had a great time participating, and look forward to the next even when I can have a pint and learn about some neuroscience from our friend Tom Taylor-Clark, at USF.

I certainly recommend coming to the event, and subscribing to the podcasts - which are available on iTunes as well as through the link here.  You can also follow Pint of Science US on G+ or on twitter @pintofscienceUS for updates.

Have a pint, talk about science.

The pre-metastatic niche is only half of the story of metastasis (it's the biological one)

Recently, Cancer Research UK posted an article on their blog in which they explain, in layman's terms, recent trends and ideas in research into metastatic spread. The focus of that article is on the concept of a 'pre-metastatic niche', the idea that the primary tumour emits signalling molecules that prime certain organs for the arrival of metastatic cells. We find this line of thought very interesting, as it could, at least in part, explain patterns of metastatic spread, but have strong opinions about how the ideas were presented and the lack of acknowledgment of the other factors that could be at play.  

First, the reader is given a condensed historical background, in which the surgeon Stephen Paget is given credit for having solved the riddle of metastatic patterns 150 years ago. His method of studying metastatic spread in breast cancer is briefly mentioned, however, as is often the case when the seed-soil hypothesis is mentioned, these old 'truths' do not seem to be carefully checked. For example, a much more recent study from by Dr. J Pickren (reported in The Principles of Metastasis by L. Weiss, p. 231, recently reviewed here), which reports a 4:1 ratio between splenic and hepatic metastases (compared to the 14:1 ratio that Paget observed). Another fact not accounted for by Paget in his analysis, is that the liver not only receives arterial blood, but also blood from the gut organs via the portal vein, thereby increasing the chance of it receiving circulating tumour cells (CTCs). If micro-metasases are present in the gut, then these secondary CTCs will most likely lodge in the liver increasing the risk of developing liver metastases. Lastly, Paget only studied a single location of primary tumours, making general conclusions difficult to draw - especially as the connectivity differs greatly between organs. These simple observations should make it clear that Paget's hypothesis is nothing more than an indication of what might be the case in certain circumstances, rather than a settled fact.

From reading the article one also gets the impression that CTCs are drawn to certain organs in the body (e.g. the caption of the 2nd figure reading "Tumour cells are selective about where they end up." or later in text "...which wandering tumour cells find irresistible."). This is not in agreement with what we know today (and have known for the last 30 years) about the dynamics of metastasis formation.

Figure 1: Human vascular system network topology schematic. It is evident by inspection of the network diagram that tumors originating in the gut and lung experience significantly different flow patterns and order in which they experience filtration at capillary beds than tumors originating in other parts of the ‘body’. The alternate pathways (purple) define the fraction of cells which evade arrest (filtration) at a given capillary bed. There are scant measurements of this in the literature, and none for clinical studies.

On the contrary CTCs have little influence over where they end up, instead the correct picture is that of a primary tumour releasing astronomical numbers of CTCs into the blood stream (roughly 100 million cells per day, of which most die in the blood stream), and that these cells are distributed according to physiology of the circulatory system. 

This means that each organ (except the lung and liver) receive a fraction of CTCs in direct relation to their relative blood supply, and only at this point, at which the cancer cells flow through the capillary bed of the organ, can organ specific mechanisms influence the fate of the cancer cell. This means that any explanation of why patterns of metastatic spread look as they do needs to first take into account the characteristics of the circulatory system, and only then the organ specific mechanisms such as the formation of a pre-metastatic niche.

These facts suggest (at least to us) that one should view the formation of the pre metastatic niche from a more passive point of view. The signals secreted by the primary tumour induce a systemic inflammatory response - which may or may not effect all organs. The evidence suggests that some distant sites respond in a way that makes them more hospitable to the CTCs that happen to pass though them and hence these cells are more likely to form overt metastases - but to present this as an active process is to stretch the data and to anthropomorphize to a dangerous extent.

When attempting to synthesize and communicate difficult scientific information to the public, it is always tempting to present a small slice of the story - and indeed, this is good practice as only so much can be communicated effectively at one time.  But when doing this, it is essential to point out where the limits of our understanding are, and not oversell current hypotheses as the 'truth'.  Science is, and always has been, a steady progression toward understanding, paved by models that are (we hope) less and less wrong.  The way we think today is not likely to be the same as the way we think in 10 years time.

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.

Review of Whole Brain Radiotherapy for Brain Metastases

Just a quick post to let you know about a review I published with two collaborators today in Surgical Neurology International.  The heavy lifting for this was done by +Emory McTyre, a very bright and motivated medical student who has recently matched into radiation oncology at Wake Forest.  This is a comprehensive review of the use of whole brain radiotherapy in the treatment of brain metastases.  It is written for a clinical audience, but since it is #openaccess anyone can read it and use the information therein.  The corresponding author is a friend and radiation oncologist at Moffitt Cancer Center, Prakash Chinnaiyan.

Here is a link, enjoy and feel free to share.

http://www.surgicalneurologyint.com/text.asp?2013/4/5/236/111301