Why does cancer spread to the spine? Newly discovered stem cells might be the key

Benjamin Thompson

Welcome back to the Nature Podcast, this week: why cancers spread to the spine...

Shamini Bundell

...and the use of MDMA in the treatment of post traumatic stress. I'm Shamini Bundell...

Benjamin Thompson

...and I'm Benjamin Thompson.

<Music>

Benjamin Thompson

The spread of cancer cells from their initial tumour site to other parts of the body, known as metastasis, is something that's common in the late stages of cancer, and is of course, a very serious issue. One of the places that metastases often develop is in bone, and certain types of cancer seem to preferentially spread to certain types of bone. For example, some metastasize to the spine, much more than the so called long bones, like the leg or arm bones. Here's Matthew Blake Greenblatt from Weill Cornell Medical College in the US to explain more about it.

Matthew Blake Greenblatt

Breast and prostate are the two classic ones, but also lung and many other solid tumours go to spine much more frequently than to long bones. In some clinical studies, there might be three or more times as many spine metastases as there are metastases to other skeletal sites.

Benjamin Thompson

And spreading to the spine can lead to some serious complications.

Matthew Blake Greenblatt

The spinal cord is right there. And if the tumour is growing in a way that causes expansion into vertebrae into the spinal cord, that leads to paralysis, it can lead to a lot of other serious problems, because we know that patients that have a fracture related to this metastasis, because this tumour is here, and it's eating away the bone, that that is a very strong risk factor for subsequent mortality.

Benjamin Thompson

Quite why these cancer cells preferentially spread to the spine has proved a puzzle that doctors have struggled to solve. One prevailing idea first developed in the 1940s was that things like coughing were temporarily changing patterns of blood flow, forcing more blood into the spine, leading to more metastases. This idea persists, and Matthew says he was taught it in medical school, but it never rang true for him. Now, he and his colleagues might be able to shed some more light on what's going on. In a recent Nature paper, Matthew and his colleagues identified a mechanism involving a newly discovered type of stem cell in the spine. In fact, the team didn't start out studying cancer at all, they were looking for stem cells. So let's talk about them for a minute. Your bones are formed and maintained by stem cells, specialist cells that can self renew by dividing and which can also differentiate into the different cell types that actually produce bone tissue. But it's not a one cell fits all situation. Different stem cells have been identified in different parts of bone. For example, in some of the team's previous work, they found different kinds of stem cell on the outside of bones compared to the inside. And this got Matthew thinking.

Matthew Blake Greenblatt

Finding that the stem cell on the outer surface and the inside of bone are different, really conceptually, opened the door to say, okay, if the inside and outside of bone have different stem cells, then why not different bones.

Benjamin Thompson

The team decided to start looking for the stem cells that make vertebrae. This is because spinal bones develop in a very different way to other kinds of bones. So they hypothesised that they might be made by different cells. Through a series of experiments in mice, they identified a group of cells that were unique to vertebrae and confirmed that they were stem cells. These cells were crucial for the development of spinal bone and weren't seen in mice limb bones.

Matthew Blake Greenblatt

You know, by focus, I'm a bone guy. And so we were certainly starting with that question of what is the stem cell, that forms of spine? I think there's a different stem cell there. And then once we had it in hand, we said, okay, why is this important? What's the clinical impact of this cell? And we had those ideas I think stewing around for a while, about how this cell may play a role in metastasis.

Benjamin Thompson

Which brings us back to cancer. By injecting breast cancer cells into the bloodstream of mice the team showed that, like in humans, more metastases went to the spine than the limb bones. And to prove this was down to the spinal stem cells and not something like bone shape or blood flow. The team used mini 3D bone structures called organoids.

Matthew Blake Greenblatt

We took the stem cell from the spine and the stem cell from limb and we put them in two different legs of a mouse one in the right leg, one in the left leg. We gave them a few weeks and because their stem cells, they form miniature bones, these round circular bone pellets basically, and those pellets have pretty much all the major features of an intact bone. And then we challenge those mice with the breast cancer cells. And when we do that, the breast cancer cells go about twice as much to the spine, stem cell derived bone, than the long bone stem cell derived bone. So that really showed that it's the biology of these stem cells driving the metastatic preference.

Benjamin Thompson

But what was causing this phenomenon? It turns out that these vertebral stem cells and the cells that derive from them secrete high levels of a protein called MFGE8. And somehow, although it's not clear how this molecule causes tumour cells to preferentially migrate to the spine, deleting the stem cells ability to produce MFGE8 drastically reduced this preference. Now, all the work we've discussed so far has been done in mice. So what about humans? In further experiments, the team looked to see whether human versions of these stem cells existed by examining tissue samples taken from people who had undergone spinal surgery. They found them and showed that the cells could form bone like tissue when implanted into mice. The human cells also produce MFGE8, which again was involved in metastasis preference in the mice.

Matthew Blake Greenblatt

Of course, we're excited because this really takes that next step toward showing the clinical relevance of this. This cell exists in humans, it's in the same place as the mouse stem cell. And using specialised models where we put these human cells into mice, it seems to play a very similar role in metastasis.

Benjamin Thompson

Geert Carmeliet from KU Leuven in Belgium, has written a News and Views article to accompany the research. She was impressed with the scale of the work and its findings.

Geert Carmeliet

Well, I think it's really beautiful work, because it's a novel concept, both that there is a new stem cell, and that it's evolved in some pathology. And yeah, they have done it very thoroughly. I mean, it's clear cut well thought through the experiments are really top.

Benjamin Thompson

However, there's a lot that isn't understood about this system. MFGE8, the key molecule in this research is what's known as a growth factor. And it's made by lots of different types of cell playing an important part in several biological processes. Geert thinks that there's a good chance that MFGE8 isn't the only player involved in metastasis preference, things like nutrient availability, and the types of cell present could make a difference. And there could be other growth factors made in and around the vertebrae too and understanding this is needed to get a clearer picture of the full mechanism.

Geert Carmeliet

I think the factors that are produced there by these cells is important to know, and likely, but of course, we can't say it for sure, this growth factor is one of them. And there will be others that work together so that there is really a microenvironment formed by the skeletal stem cells by the cells that are coming from the stem cells. And these microenvironment will then determine not only the survival of the tumour cells, but also the proliferation, expansion and interaction with the other cells.

Benjamin Thompson

Matthew also says there's still a lot to learn about this system, but he's hopeful it could provide new insights into why some cancers prefer to spread to the spine, a question that has puzzled doctors for years. He and his colleagues are looking for ways to block this happening, which in time could lead to new therapies. And perhaps knowing that this group of stem cells exists might help in other areas too. And the team are collaborating with surgeons to try and improve outcomes for people undergoing back surgery, having vertebrae fused together, for example.

Matthew Blake Greenblatt

As you can imagine, the stem cell that forms the spine is really a central interest for a spine surgeon. Everything they deal with in theory, you know, could be driven by the stem cell, okay? We talked about cancer, but there's this whole huge and immensely clinically important practice of spine orthopaedics, does this stem cell drive the spine fusion, that was the procedure that we got these tissues from to begin with? Is it giving rise to those cells that actually glue the vertebrae together? So those are the sort of things that we're working on with them.

Benjamin Thompson

That was Matthew Blake Greenblatt from Weill Cornell Medical College. You also heard from Geert Carmeliet from KU Leuven. To read Matthew's paper and Geert's News and Views, look out for links in the show notes.

Shamini Bundell

Coming up how the world's most powerful X ray laser will help researchers study ultra fast processes at an atomic level. Right now though, it's time for the Research Highlights with Nick Petrić Howe.

Nick Petrić Howe

Male Palm cockatoos make musical instruments to impress females. And now researchers have figured out what kind of tuneful tools they prefer. A lot of animals use tools, mostly to forage for food, but male palm cockatoos drum to their own beat, making seed pods or sticks into instruments for tapping against trees. They do this to attract females, and so researchers looked at 256 of their drumsticks to see which they prefer. They found that individual cockatoos would consistently choose similar kinds of instruments based on length, width and mass. Whether or not their preferred acoustic apparatus was close or easily available, didn't seem to make a difference, each cockatoo would still pick its preferred material. The researchers concluded that this shows that Palm cockatoos make individual creative choices, something quite unusual for the animal kingdom. Listen out for that research in the proceedings of the Royal Society B.

Nick Petrić Howe

How far apart do you stand from others when waiting for a train? Well, according to a new mathematical study, it's probably around one to 1.2 metres. On a busy train platform, lots of people squished together can make things uncomfortable, and can even affect how quickly the train is able to leave. With public transport use set to increase in Central Europe, researchers in Germany wanted to understand the spatial distribution of passengers waiting on a platform. To do this, they set up a mock platform and got participants to wait for a fictional train. They varied up how many people were waiting, how long they waited, and even whether or not there were obstacles. Despite these changes, people kept a consistent distance apart. The authors use this to develop a mathematical model of the attractiveness of different places to wait and say they could use this to optimise busy railway platforms. Wait for that research, one metre away from me, over at the Journal of the Royal Society Interface.

Shamini Bundell

Finally, on the show, it's time for the Briefing Chat where we discuss a couple of stories that we've read about in the Nature Briefing. And today I've been reading an article in Nature based on a Nature Medicine paper about the use of MDMA to treat Post Traumatic Stress Disorder.

Benjamin Thompson

Right, so, MDMA, then it's also known as what ecstasy and Molly in the US and it's a controlled substance in most of the world, right?

Shamini Bundell

Yeah, it's a psychedelic drug. It is an illegal drug, which makes it quite hard to study. But this is actually the second big clinical trial that used it in combination with psychotherapy, to treat people with post traumatic stress disorder or PTSD. So basically, they would be having a sort of specific kind of psychotherapy, either with or without MDMA, as well.

Benjamin Thompson

I mean, we've talked in the podcast a few times about different psychedelic drugs, LSD and psilocybin, from magic mushrooms that seem to have this kind of potential for treating different mental health conditions. And this is another one to add to that list then.

Shamini Bundell

And it's been sort of moving along for a while. So this is the second after a 2021 trial showed the same thing. But basically, the FDA in America, that's the US Food and Drug Administration require generally to placebo controlled trials before they will approve a drug. So they've managed to get their second trial, which has just come out recently, and found similar results to the first one, which in this case, 71% of people who received MDMA, alongside the therapy lost their PTSD diagnosis, whereas those who received a placebo plus the therapy 48%, lost their PTSD diagnosis.

Benjamin Thompson

And so trial then is what's been published, I mean, these seem like positive numbers.

Shamini Bundell

Yeah, and this is from maps that Multidisciplinary Association for Psychedelic Studies. And you know, based on the numbers from this one and the 2021 trial, they say that they want to seek formal FDA approval for the use of this treatment before the end of this year. And they've sort of put it in a treatment category, that means it could be evaluated very quickly, which would, if approved, that would mean that MDMA is no longer actually strictly illegal in the United States, as it is right now. And that will then also as well as potentially being able to be used in treatment mean it's actually easier to study these effects, do large clinical trials, maybe figure out what different groups it might work in, why it might not work for some people, whether they're sort of different types of therapy, different contexts, that it may have different impacts in. So you know, there is still a lot of work to be done. But this approval would certainly go some way to allowing that work to happen more easily.

Benjamin Thompson

Well, I'm sure lots of discussions will have to be had in various places before that decision is made. But what are researchers saying about the trial as it stands?

Shamini Bundell

So I think the researchers who've been involved in this, the researchers who've done the study, are pretty pleased with it. One of the most promising things that they've highlighted is there was a really low dropout rate for about 100 people, and only 9% of participants left the study, which does contrast with previous studies on PTSD psychotherapies. And the neurologist who led the studies point out that it's not because the MDMA makes the therapy more fun, but that the drug itself she calls it a communication lubricant that basically allows people to recall these traumatising events and talk about them without experiencing shame or horror. So that's a sort of potential mechanism for what's actually going on here. And other researchers also quoted in this next article, say, yep, this is, you know, really important work. It's good that this is the sort of second replication of this. They are small trials, but the improvement in symptoms is quite large. So it's sort of statistically significant because of that. But it's also limited, so for example, in these trials they were three of these sort of therapy sessions with or without the MDMA. And then they sort of reviewed after that. So one question could be whether these effects will last long term, obviously, that question I sort of alluded to earlier of like, does this apply to everyone? This work does seem to show that across racial and ethnic groups, it does seem to work equally well. And one really interesting element that people brought up was whether you can say that this is a blinded study or not, because 94% of the people who were in the group that got the MDMA, guessed that they'd got the MDMA because obviously, it's a really intense psychedelic drug.

Benjamin Thompson

Yeah, hard to sort of put that down to the placebo effect, I suppose.

Shamini Bundell

Yes. And even in the placebo effect, actually, 75% of people who got the placebo, correctly guessed that they'd got the placebo. So in that sense, they will not blinded and there's a strong effect that if you think you've received an active drug, people tend to feel better, people are more likely to sort of report an improvement of symptoms. Although they did blind, a sort of independent evaluator, who was basically evaluating the participants before and after to see how they improved. And those people did not know whether or not the patient they were examining had the drug or the placebo. So that element was blinded. And that was something special, that they'd set up and got some special FDA approval to do it for this particular study, because of that big issue.

Benjamin Thompson

I mean, I guess at this point, it's certainly worth saying that this is a controlled clinical trial involving medical professionals and and all the rest of it. And this isn't carte blanche for people to go out and self medicate?

Shamini Bundell

Absolutely. So in the future, there's sort of these regulatory questions about what the FDA is going to do. But in any case, like this trial is about, as you say, carefully controlled conditions in the context of therapy. The researcher on the trials, has said she's a bit worried that people might go off and just try MDMA on their own, there's of certain situations in which that can be especially harmful if you have a heart condition. For example, it hasn't been tested and people with, for example, history of schizophrenia, which could potentially be triggered. And of course, in this study, if people have a bad reaction to taking the drug, they're in obviously a much safer environment.

Benjamin Thompson

Well, a fascinating story that one and I guess we'll add that to the somewhat growing list of evidence that certain recreational drugs may have therapeutic uses, as well. But for the time being, let's move on to my story this week, and it's one that I read about in Nature and to be honest with you it couldn't be more different. It's about an x-ray laser in the US, which has been upgraded to become the most powerful in the world. And when it's up and running, it will produce 1,000,000 x-ray pulses a second and it should help researchers probe ultra fast processes like electrical charges, hopping between atoms and things like that.

Shamini Bundell

I really wanted you to explain all of that in like a supervillain monologue style about the 1 million x-ray pulses. I will take your word that this is not a super weapon, it is in fact, for legitimate scientific purposes. But tell me a bit more about what the purposes of the giant x-ray laser actually are.

Benjamin Thompson

Well, totally reasonable and let me give you a bit of background. And so this x-ray laser produced its first beams last week, and it's actually a $1.1 billion upgrade to the Linac Coherent Light Source, the LCLS. And what this machine kind of does is it flashes really fast pulses of x-ray okay at a sample and it's kind of like a strobe light, okay, so you get these individual snapshots in time of things happening, like molecular processes in many cases. And by putting these snapshots together, you can make almost flipbook style movies of things happening. And these happen really short timescale. So we're talking in many cases like femtoseconds.

Shamini Bundell

Really fast and really small there.

Benjamin Thompson

Atomic level, absolutely right.

Shamini Bundell

And so this has already been an x-ray laser that's been doing this for some time, then?

Benjamin Thompson

That's right, so the original LCLS, LCLS1, I suppose, started in 2009 and it was the first instrument to combine the atom probing capabilities of high energy x-rays known as hard x-rays and the laser speed, okay. And the way it works is kind of like this, right? So this original facility had a three kilometre long particle accelerator, okay, the file electrons through a copper pipe, and magnets made these electrons kind of wiggle backwards and forwards kind of like a snake, I suppose, right. And this is what fired out these x-rays towards the sample and allowed the researchers to get these little snapshots of what was going on. Now, according to the article, the researchers when they built this wasn't sure if it was actually going to work at all. And it did. And since then, a bunch of these facilities have been built around the world. But this one in the US, as I say, has been upgraded now. And the way they've done this is they've upgraded part of the copper pipe, right? They've replaced it with some cryogenically cooled sections that are super conductive at really, really low temperatures like 2 Kelvin, so like really low. And this reduces the resistance to nearly zero, and helps the upgraded instrument achieve an even faster x-ray pulse rate.

Shamini Bundell

So then your little flipbook glimpses at whatever is going on in the sample, you've got more sort of images per second, then?

Benjamin Thompson

Yeah, it seems like that's going to be the case and it should allow chemists and biologists to make you know, molecular movies that are crisper than ever seen before. And, and it could be used for some interesting things. Scientists seem quite excited about this. So one researcher in the article talks about how to use the original instrument, okay, and another one in Japan, to reveal how a protein complex called photosystem 2, which is involved in photosynthesis, splits water and produces oxygen. Now, this, of course, is a really, really important process—

Shamini Bundell

—seems important, yeah—

Benjamin Thompson

—and they tracked how the structure of some metal atoms changed through different energy states, which is kind of mind blowing, they could do that. And they want to use the new facility to get even more of an insight into what's going on, like how the charge is distributed within these atoms, and how the electrons are spinning and things like that, which they hope could be used in future to try and mimic this obviously, fundamental process in other ways.

Shamini Bundell

That level of detail is amazing. So this has now been switched on, it's getting switched on?

Benjamin Thompson

So it has produced its first beams, but it's being ramped up. And they're working out how they can get it to potentially a million pulses a second. And it should have some other benefits, too. So, the power of this machine should mean that researchers can use more dilute samples, which is important because when you're dealing with these molecular complexes, you have to get quite a lot of them in some cases to look at them. And these things can be vanishingly rare, so being able to use less than just means less work.

Shamini Bundell

So future Briefing Chats, it's going to be various results coming out of this newly upgraded x-ray laser, then I guess?

Benjamin Thompson

Yeah, so apparently the team are evaluating proposals from around the world to use the new system. And also it has to be said, there are other facilities like this being built that could be equally or more powerful. And there's a nice quote here saying that I'm sure will be leapfrogged. One of the researchers is saying that the record is there now, but someone else will be that at some point, and then they'll beat it again. And off we go. But interesting times in this field.

Shamini Bundell

Well, if there's any of our listeners out there who are sort of putting in applications for this super powerful x-ray laser, we shall keep our fingers crossed for your projects and look forward to hearing about them in the future. I think that is all we have time for now. For more on these stories, check out the show notes we'll put some links up. And also a link where you can sign up to the Nature Briefing and get more like these.

Benjamin Thompson

And that's all for this week. As always, you can keep in touch with us on X, we're @NaturePodcast, or you can send an email to podcast@nature.com. I'm Benjamin Thompson...

Shamini Bundell

...and I'm Shamini Bundell. Thanks for listening.