Decoding cancer cell communication

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

Many of the most common cancers that exist need a specific molecule to grow and spread. In other words, they’re addicted to these molecules for their survival. So, the hope is that stopping these molecules will perhaps force the cancer to die.

Professor Elizabeth Vincan is a Senior Medical Scientist and Researcher at the Doherty Institute for Infection and Immunity, with joint appointments at the University of Melbourne’s Doherty Department and the Victorian Infectious Diseases Reference Laboratory.

Twenty years ago, Professor Vincan set out to understand how to curb cancer’s addictions. Her research group was among a number to realise that some cancer cells always ‘switched on’ specific genes that function in an ancient form of cell-to-cell communication. And the idea was that if you could find out what these genes did, and block them, it could provide a new way to treat cancer.

Professor Elizabeth Vincan took some time out to chat about her work with Dr Andi Horvath.

ANDI HORVATH
Professor, you get around. You're in the area of cancer research, right?

ELIZABETH VINCAN
Yeah, so that’s – I fell into that really in the late 1990s coming from a signal transduction background which sounds like a really complicated word but really all it means is how cells communicate. So really it’s – cells need to know what to do, where to be, where to go, and that’s what signal transduction is.

At that time I was a young post doc mum and working where I was working was just too difficult because I had to go over the West Gate Bridge. Then a position came up at Western Hospital that suited me and I fell into cancer research. The good thing about that is that I don’t actually have any formal cancer training. I never learnt it in the same way that other people do. So when I address a question I come at it from a completely different tack. So that has been instrumental in the path that my career has taken.

ANDI HORVATH
Right. So you went from how cells communicate with each other – were you working on a particular communication system?

ELIZABETH VINCAN
That particular communication system was – this is a big word, phosphatidylinositol signalling at the Baker (The Baker Heart and Diabetes Institute) and cardiac myocytes.

ANDI HORVATH
Good grief. That might be sexy to some people but unpack it for us.

ELIZABETH VINCAN
It was very sexy at the time and it’s all very sexy but I learnt the fundamentals of how to do signal transduction. I had an incredibly fabulous mentor, Professor Elizabeth Woodcock. It meant that I took those skills when I sort of fell into this new communication pathway called Wnt signalling. Now this particular pathway is really important in developmental context, so embryogenesis…

ANDI HORVATH
So when the cells talk to each other – when they're an embryo and says, right, we’re going here, we’re going there, what are you doing, so that what that big long word is about.

ELIZABETH VINCAN
That’s what Wnt signalling is. That’s exactly where – the pathway that I ended up falling into. In the mid-1990s, two major pathways collided. Developmental biology and cancer.

ANDI HORVATH
Now, explain that for us because in both of those situations there’s a lot of cell growth going on. You were instrumental in actually bringing those two concepts together to see if there’s…

ELIZABETH VINCAN
Common…

ANDI HORVATH
...similarities.

ELIZABETH VINCAN
Exactly. So there are a lot of common pathways, common processes in Wnt signalling which is my…

ANDI HORVATH
That’s in the cancer cells?

ELIZABETH VINCAN
Which is my…

ANDI HORVATH
Yeah.

ELIZABETH VINCAN
...pathway. Is very important in the developmental context. But really growing – what I realised way back in the late 1990s is that growing – a solid tumour, for example, is very similar to growing an organ in the body. The same pathways are involved. But everyone thinks of cancer as uncontrolled growth. In fact, it’s actually the opposite. In cancer this pathway is really constrained. Because if you think about in just simple terms we go from two or three cells to being a three and a half kilo baby in nine months. If we had a tumour growing that fast and if that pathway was as active in the adult we’d actually kill the host. Cancers couldn’t survive. So this concept that it’s not uncontrolled, it’s actually far more rigorously controlled and constrained has been a concept that the cancer biologists had to get past and that’s what my work has done.

ANDI HORVATH
So you’ve got a really fresh look at how cancer works. You weren’t stuck in the dominant dogmas of what the cells were doing. You brought in new thinking into that. Where did that lead?

ELIZABETH VINCAN
Because I’m part of the Wnt community internationally so I’m internationally recognised with the – my lab, I should say, is internationally recognised for the work that we’ve done and even though I’ve been working on it since 1999, at least the concepts, it actually got recognised earlier this year so it’s taken a long time. We published in cancer research in March earlier this year. We made the cover of the journal. My team provided pharmacological and genetic proof that we actually get signalling from outside the cell, in a cancer cell, even though there’s mutations to the intracellular parts of the pathway that activate. Now, this concept was really difficult because people focus on just the genomics, and so once something’s mutated they though the pathways activated. End of story.

ANDI HORVATH
Okay. Let me unpack that again.

ELIZABETH VINCAN
Yeah.

ANDI HORVATH
So the cell has genetic mutations that we know are associated with cancers but what your team was suggesting was there was an outside signalling from the cell that actually makes that happen.

ELIZABETH VINCAN
Precisely. In fact, what our work has shown – and others – this is all coming together beautifully, just all the pieces of the jigsaw puzzle are falling into place. What we’ve shown is that, in fact, those genetic mutations that initiate cancer make the platform. On top of that there’s my genes and when we actually block my gene which is – that I’ve been working – my lab’s been working on, Frizzled-7, if we block that we actually hit cancer on the head. Now, that to me is – has just been wonderful.

ANDI HORVATH
Let’s define Wnt.

ELIZABETH VINCAN
Mm-hm.

ANDI HORVATH
We’re going to be using this word a lot.

ELIZABETH VINCAN
A lot.

ANDI HORVATH
What is Wnt?

ELIZABETH VINCAN
So Wnt is a growth factor which is a communication, cell-cell communication molecule and it’s ancient. It’s conserved through evolution…

ANDI HORVATH
So we find it in early mammals.

ELIZABETH VINCAN
Early – even less than mammals. It’s a pathway that has been mostly defined in developmental context. So no one could have envisaged back in the 80s and the 90s that a pathway that’s important in worms, in flies, in mice, in all sorts of lower animals will actually end up being therapeutically targeted and interrogated for anticancer treatment in this decade and the decades coming.

ANDI HORVATH
Right. Because it’s associated with cell growth.

ELIZABETH VINCAN
Cell growth.

ANDI HORVATH
Let’s define Frizzled-7. What's Frizzled-7? It’s a cute name.

ELIZABETH VINCAN
The names come from the fly people. Fly geneticists have a wonderful sense of humour so basically when they did the genetic studies in flies, the fly that had the Frizzled mutation look frizzled. Literally the word means, frizzled. Just like we look like the night after a [laughs]...

ANDI HORVATH
It’s like a bad hair day basically.

ELIZABETH VINCAN
[Laughs] A bad hair day.

ANDI HORVATH
Right. These guys had a bad hair or bad bristle day.

ELIZABETH VINCAN
In fact, it was bad bristle day. Then those obviously names now are taken on into the mammalian context. But as humans we’ve got – as mammals we got 19 Wnts and 10 Frizzleds. So Frizzled is the cell surface receptor. So it’s the molecule that receives the growth factor signal.

ANDI HORVATH
The Wnt.

ELIZABETH VINCAN
The Wnt.

ANDI HORVATH
I see.

ELIZABETH VINCAN
So there’s 10 of those, 10 Frizzleds, and they're an incredibly interesting family of cell surface molecules and they have quite defined functions. We focus on Frizzled-7 because it just kept popping up in development context dictating this and that. Also it is the only Frizzled of the 10 family members that is consistently expressed in every stem cell population studied. And also during this time people in the Hans Clevers group, Nick Barker and – those – my colleagues, showed that cancer actually starts in the stem cells. The cancer cells take this need for Frizzled-7 and hijack it for their own purpose. Now, that is why we can block cancer growth by blocking Frizzled-7.

ANDI HORVATH
Got it. So let me see if I’m a good student and I’ve passed my exam.

ELIZABETH VINCAN
[Laughs]

ANDI HORVATH
The cell has a mutation inside it that causes cancer but on the surface of the cell as made by its own genetics, the cells genetics, is a receptor that accepts signals from other cells. We’re calling that the Frizzled-7 receptor. Wnt comes along and says, woo-hoo, this is what you guys should be doing. So there’s an interaction between Wnt, Frizzled-7 and that is where we’re targeting cancer treatments at the Frizzled-7 receptor.

ELIZABETH VINCAN
Precisely.

ANDI HORVATH
I understand cancer [laughs].

ELIZABETH VINCAN
So Genentech, I mean are going – can I say gangbusters?

ANDI HORVATH
Yeah.

ELIZABETH VINCAN
With making peptides that specifically inhibit aspects of Frizzled-7 signalling. So we’re trying to separate the good signalling from the bad because obviously stem cells need it. But also what my team showed was that, for example, in your gut your lining can take a hit from knocking out Frizzled-7 and you recover – the intestine recovers because one of – two of the other family members come up and…

ANDI HORVATH
Rebuild it, do they?

ELIZABETH VINCAN
...compensate – compensate for Frizzled-7. They don’t do it as well but they will make the epithelium recover. However, cancer doesn’t have the same mechanism. So once you knock out Frizzled-7 there’s no compensatory mechanism. So you knock out Frizzled-7, they don’t grow.

ANDI HORVATH
That’s convenient because it means we don’t knock out the whole body.

ELIZABETH VINCAN
Exactly which means – so there’s Frizzled-7 antibodies already in clinical trials, phase two clinical trials and what really our recent work showed was that it’s not just for cancers that don’t have a mutation inside the cell. It’s for all Wnt-addicted cancers. Now, that was the real take home message from our work. People sort of think, okay, so we’ve got a mutation inside the cell, no need for the top. But if we don’t have a mutation in the cell then we need signalling from the top. It actually doesn’t work like that. We need signalling from the top whether we have a mutation inside the cell or not.

ANDI HORVATH
So you’ve completed the picture of why some cancers don’t have the gene. It’s about cell signalling. So right now we’re recording in November 2019, there are clinical trials going on.

ELIZABETH VINCAN
Yes.

ANDI HORVATH
Tell us about those.

ELIZABETH VINCAN
So far the clinical trials are using the Frizzled-7 –anti-Frizzled-7 antibodies have focussed on cancers that don’t have a mutation inside the cell in the same pathway. So really what our work has shown is that it doesn’t matter whether it’s – there’s a mutation inside the cell or not in the Wnt signal pathway the anti-Frizzled antibodies will work. And we actually – cancer research asked us to write a review to place our unique finding into the broader cancer context. So my team did an unbiased search of publicly available genomic starter and we mapped tumours that have Wnt addicted tumours and then calculated the percentage of aberrations at the cell surface and then the percentage of aberrations inside the cell. All of them had both. Which is exactly what we’ve been working on for 20 years. [Laughs]

ANDI HORVATH
What a relief.

ELIZABETH VINCAN
So it was just superb. I mean I was just – yeah.

ANDI HORVATH
You found the other side of cancer treatment which wasn’t just the genes. It was the cell surface.

ELIZABETH VINCAN
So now, everybody – this is a world – this is a global movement. I mean, everybody’s moving towards phenomics and epigenomics because cells…

ANDI HORVATH
You might need to define those. Phenomics, what's that?

ELIZABETH VINCAN
Phenomics is what the cells look like. So you can have all the genetics in the world but at the end of the day where that cell is…

ANDI HORVATH
Because gene expression is complex. Not all genes get expressed in certain ways so even though the map's there, the look might be different.

ELIZABETH VINCAN
The look might be different. It depends on where that cell is and it’s influenced by its environment. It’s influenced by what's actually impacting on it. Now, those sort of changes depending on what they are might be reversible. So it can't be a mutation because a mutation is irreversible. The bits of the genes that actually start making the gene products are modified so that they're not expressed or they're amplified or various other mechanisms. We now have high throughput platforms for looking at what the cell looks like. Also looking at what are these other changes that are not genetic mutation but changes to the blueprint, changes to the DNA and that is really exciting.

ANDI HORVATH
In the 1990s and early 21st century we were asking the question, why can't we cure cancer? How’s it looking from now on?

ELIZABETH VINCAN
I’m really, really enthusiastic and optimistic for the future and one of them is because of these types of studies. But what really has made these sorts of studies possible – because we eventually have to go into a human, a human context. There’s all sorts of examples where mice – even primates don’t accurately predict how humans respond to a certain drug. The real breakthrough, as everybody knows, is organoids and that actually started with Professor Hans Clevers in The Netherlands. Really, it started with Nick Barker in his laboratory discovering the marker, an exclusive identifier of adult stem cells in the gut.

ANDI HORVATH
Okay. Let’s talk about organoids. Organoids are kind of like miniature versions of clumps of cells that resemble the organs in our body.

ELIZABETH VINCAN
The organs in our body have stem cells and those stem cells know what they have to do. In hindsight, this is so obvious [laughs] but obviously wasn’t obvious until the experiments were done. But if you take out a stem cell from your intestine, for example, put it somewhere else it will still make intestine. It knows it has to make intestine. So in many ways this is sort of like when cancer spreads to other organs. Like an ovarian cancer will still make an ovarian tumour in the lung or wherever it goes.

So really that actually really blew the field open because now we could actually grow replicas in a petri dish of human tissues, normal, but also tumour-derived organoids. There was a publication just recently, earlier this year that showed that the response of the organoids in a tissue culture matches the response of the patient to a particular drug. So in a two or three week turnaround time we can actually work out which drug will work on a particular person. Now, that means they're treated with the correct drug from the outset, one, but secondly, they're not treated with something that isn’t going to work on their cancer anyway. All drugs have some level of side effects. It just means that this is now a reality. We can genuinely personalise anticancer treatment to the individual. Now, that is just ground-breaking.

ANDI HORVATH
You’ve allowed this to arrive.

ELIZABETH VINCAN
[Laughs] A small chink, a small piece of the puzzle.

ANDI HORVATH
Let’s talk about the various inspirations you’ve had on this journey. I mean, you came to cancer through the eyes of biochemical signalling between cells. What else inspired you to enter this area besides finding a hospital [laughs] that’s close to your home?

ELIZABETH VINCAN
It was actually going to my first Wnt meeting in 1999. I mean, at that time I was one of a handful of cancer biologists. The two fields had just collided and everybody else was a development biologist and there were people talking about Dictyostelium and flies, frogs, you name it, all sorts of work. But the sort of processes that this pathway regulates just called out cancer, cancer, cancer, because almost at the same time a very clever pathologist in Germany called Thomas Brabletz, he was a pathologist, medically trained, and did his PhD in a development organism called the sea urchin and was looking at the Wnt signalling pathway in the sea urchin. Then when he looked at colon cancer tissues he noticed very similar staining for the effector of Wnt signalling which is called beta-catenin. It doesn’t really matter but it means that the levels of this particular effector were not homogenous. They varied through the tumour.

He made the connection that this very similar to the patterning that you have in developmental contexts. So he coined the term, I think, neo-morphogenesis. That’s how I fell into it as well. Because my gene – we ended up getting – purely serendipitously, one of my experiments gave us data that I just could not understand. I was trying to market this for a grant at the Cancer Council of Victoria and I just didn’t know how to market it. My partner, who is really savvy on the internet, found this neo-morphogenesis paper in some non-descript archives of something or other journal and boom. Then within no time at all the field, which is a cancer field, picked up Thomas’ work and, yeah, the rest is history.

ANDI HORVATH
You’ve got to love a dollop of serendipity.

ELIZABETH VINCAN
[Laughs]

ANDI HORVATH
So you drew together this neo-morphogenesis – in other words he identified essentially the Wnt family.

ELIZABETH VINCAN
Yeah. Yeah. It’s really – I mean, people – it’s really hard to sell something like that when there’s no precedence. At the end of the day a committee who decides on grant funding can only go by what they're presented and if you have no evidence it’s really hard to sell it. So finding this little non-descript paper that actually matches the findings and then within – now, it was in 1998 was that paper, by 2001 he was already publishing in PNAS and really revolutionised cancer – colorectal cancer metastasis so spread to other organs in the body. In the end I collaborated for a number of years.

ANDI HORVATH
So it’s hard to do a paradigm shift in thinking when there’s no evidence for that new paradigm. That’s quite a feat, Elizabeth.

ELIZABETH VINCAN
Somebody has to believe it [laughs] and fund it.

ANDI HORVATH
Someone has to give it a go. Alright. That’s amazing. What sort of changes have you seen in your field that you’ve been excited about?

ELIZABETH VINCAN
They’ve been enormous. I mean, within my career time I’ve been able to see the discoveries from our research go into the clinic whether it’s a pre-screen for cancer, whether it’s a new therapy. Now, we haven’t actually done all of that work but we contributed parts of the jigsaw puzzle that helped work out exactly how to use – for example, anti-Frizzled-7 therapeutics, will it be tolerated. All that sort of stuff comes from work that we did in mice and the power of mouse transgenics. You can't really sort out the function of a gene unless you use mouse transgenics because it’s in vivo. Growing a 3D tumour is very complex. But once those studies are done then you have to go into a human context and that’s where the human organoids have just been revolutionary. It was a Nature method of 2017. There’s a keystone meeting January 2020 just on using organoids for modelling infection and human disease. I mean, the field has just gone gangbusters.

ANDI HORVATH
Gangbusters.
[Laughter]

ANDI HORVATH
Elizabeth, what surprised you about your research? What has pleasantly surprised you or caught you unawares?

ELIZABETH VINCAN
Just – my wonderful, wonderful team. I know – whenever you're writing a grant or you're writing an application it’s all me, me, me but it’s not me, me, me. It’s actually my team, my team, my team. The way they feed off each other, the way they work together is phenomenal. The way that I run the lab is we work really hard, we work to deadline, and then we really celebrate every single success because they're few and far between.

ANDI HORVATH
Obviously you’ve got a reputation for your lab parties then.
.
ELIZABETH VINCAN
We do. I’ve got bottles of champagne where we’ve celebrated publications and I have actually now a bottle of champagne from the 2018 Wnt meeting in Heidelberg, Germany that’s signed by the real gurus in the field. I mean, I’m just – to me that’s priceless.

ANDI HORVATH
That’s better than any trophy award.

ELIZABETH VINCAN
Yeah. To be honest, I’ve never ever applied for a trophy or an award. Just simply because I just didn’t have the time. I mean, we were too busy trying to get funding, making sure that everybody had a job, that was – yeah, just never had the time for that time.

ANDI HORVATH
What advice do you give to your students?

ELIZABETH VINCAN
I’ve been instrumental in making sure that whoever leaves my lab goes to a good lab. So my advice to – when you're finishing a post doc or whatever stage you are in your career, really do your homework. Over the years you can actually land in a good place and you can land in a place that doesn’t really support you. I’ve made sure that my guys have landed in really good places and they're doing brilliantly in their own right now.

ANDI HORVATH
Fantastic. The family goes on.

ELIZABETH VINCAN
Yeah. Yeah, and we still collaborate and we still Skype and celebrate our little successes [laughs].

ANDI HORVATH
Just like your cells are signalling to each other, you still connect.
[Laughter]

ELIZABETH VINCAN
Very good.

ANDI HORVATH
With signals.

ELIZABETH VINCAN
Very good.

ANDI HORVATH
Professor, next time we see a cancer story in the news or discussions about cancer or funding promotions in public what would you like us to think about?

ELIZABETH VINCAN
I would like it to be just a little bit more transparent. So lots of things say that it’s a cure but actually – or the new breakthrough. It actually isn’t. Also just to have a look at just how much funding goes into one particular cancer especially when it comes to a small population like Australia. I think there’s a disproportionate level of funding. Although I think all cancer research should be stupendously funded. But there’s a disproportionate funding and often it’s actually through good promotion and media which is great. But I just wish we had it for some of the other cancers like colon cancer which is – liver cancer is really an atrocious outcome for patients. Really, there’s not enough resources thrown at liver cancer which is why I’m actually really encouraged by media, actually. Like the - Carrie Bickmore’s…

ANDI HORVATH
Public campaigns.

ELIZABETH VINCAN
Public campaigns for brain cancers. Lots of cancers don’t actually have the support that some of the other cancers do. It’s been absolutely wonderful that all the headway has been made. But really, take a cancer breakthrough with a grain of salt, and then Google – I mean I Google a lot [laughs] and you find out – you actually find out a lot about the real nuts and bolts numbers. There’s fantastic websites. There’s Cancer UK – I think there’s nothing worse than thinking there’s a breakthrough around the corner but it’s actually 10 years away and you’ve got six months. However, if I was a cancer patient I would put my hand up for every trial, donate all of my tumours, organs, whatever because that’s what really keeps the field moving.

ANDI HORVATH
Professor Elizabeth Vincan, thank you.

ELIZABETH VINCAN
You are most welcome [laughs].

CHRIS HATZIS
Thank you to Professor Elizabeth Vincan, Senior Medical Scientist and Researcher at the Doherty Institute for Infection and Immunity, University of Melbourne. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on November 12, 2019. You’ll find a full transcript on the Pursuit website. Audio engineering by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2020, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.