“If I see a chance, I take it.”

Wouter Karthaus is a Tenure Track Assistant Professor at EPFL’s School of Life Sciences (Swiss Institute for Experimental Cancer Research – ISREC). His research focuses on the biology and cancer development of steroid hormone-regulated organs, such as the prostate, mammary gland, and endometrium. His lab takes a multidisciplinary approach, combining organoid cultures, mouse models, genomics, and single-cell techniques.

What led you to science?

I have been fascinated by biology since I was young, and in high school, I developed an interest in chemistry. These interests merged into molecular life sciences, which I pursued in my Bachelor and Master degrees in the Netherlands. During my masters, I went to Johns Hopkins in Baltimore, where I worked on prostate cancer for the first time.

After that I returned to the Netherlands for my PhD at the Hubrecht institute in the lab of Hans Clevers, where I initially worked on stem cells in the gut, and combined that with what I knew about prostate cancer to develop a model for growing a mini organ of the prostate in a dish. This system gained popularity in prostate cancer research, and I went to Charles Sawyers’ lab for my postdoc, where we developed an organoid model of prostate cancer that evolved from drug-sensitive to drug-insensitive and found that inhibition of two pathways, JAK-STAT and FGFR, could make the cells drug-sensitive again.

Instead of having a defined career plan for years on end, I’m kind of like a stick in the river, and wherever the river flows, I will end up – provided I see the opportunity. There’s a song by Steve Winwood, while you see a chance, you take it. I try to live by that: if I see a chance, I take it.

Are you using organoids to make as realistic as possible a model of the human prostate?

Yes – and that is the first step. But to improve the system, we need to make it more true to the real organ, as prostate cells are long-lived and divide slowly, and we currently grow them rapidly in the dish. We are trying to rewrite the instruction book for growing the cells in the dish by changing the way we culture them with growth factors. We want to make it more like the real organ in the body, like coding for a computer program.

We want to have as realistic as possible prostate cancer models where we can ask questions about how cells respond to drug treatment, and how does a cell become resistant to the drug treatment. When you treat a prostate cancer cell with anti-testosterone therapy, and in principle there's three choices: One, it dies. Two, it persists – which means it's not really doing anything, it just kind of sits there. It doesn't divide, doesn't grow. Three, it is resistant. It doesn't care about the drug. And this persisting state is a precursor state to resistance. By using these organoid systems, we are trying to figure out how do these prostate cancer cells persist and how do they become resistant?

Everybody has a unique cancer; the DNA is mutated in a unique way and for prostate cancer. Of the top of my head, I can probably tell you about 30 to 40 different ways that DNA can mutate and you get prostate cancer. As a consequence, the evolution of the prostate cancer can also vary highly between individuals. So, we are asking what mutations matter in the persisting and resistance states? Does the mutational starting point matter or is there always a similar tumor evolution that will make them resistant?

Are you using genomic analysis?

There's a lot of genomics out there; what we are trying to do is make these genomic alterations systematically: we make a tumor evolution where we know the starting point, and give it a single mutation. Let's say we have mutations A, B, and C. From the same population of cells, we can make mutation A and one mutation B, and the other mutation C. And then we can analyze them step-by-step and see how the tumor evolves and ask questions about drug resistance and persistence.

Obviously, there are a lot of molecular techniques that feed into this, but our ultimate goal is to make the current therapy more effective; if the cells become resistant, can we find new therapies against them, or can we prevent the resistance altogether just by understanding how the tumor evolves?

What are the highlights of your career so far?

I think I’ve made three really nice contributions. One is making the system that really made a whole new modeling method for prostate cancer research, and there are now a hundred of labs that use my technique. I'm very proud of that one.

Another one is that we now understand how a differentiated prostate cancer cell or a normal prostate cancer cell can actually become persistent. And we know now pretty well how these ‘choices’ are made on a molecular basis, through two signaling pathways, the JAK-stat and the fibroblast growth factor receptor (FGFR). We just don't know which one is going to be the most important one. That's the question we are asking. But this concept of persistence has also been taken up by many labs. We were the first to come up with this; which always sounds a bit cocky to say you’re the first. But they're now designing a Phase 1 clinical trial, so they're actually trying to take this to prostate cancer patients; there's a company in the US that has made a new FGFR inhibitor and they intend to use it on prostate cancer patients.

What techniques are you using?

We mainly use organoids, but we analyze them using a variety of techniques. Using single-cell RNA sequencing and ATAC sequencing to understand the cells' transcriptome and chromatin structure. We're also developing live imaging with single-cell resolution to observe the choices cancer cells make in drug-resistance states. We have a technique to color-code cells based on their state, so we can see where drug-resistant cells arise in real time. We use genomic editing to give cells specific colors, which allows us to study how normal cells respond to drugs. We have different colors for different persistent and resistant states, as they come in many different 'flavors.'

Are you working with any of the Core facilities?

Organoid culture is actually ridiculously expensive, so we work with the Protein Core facility, trying to limit the costs. They are phenomenal in making recombinant growth factors for organoid culture. We also work with the animal facility now and, in the future with sequencing we will work with the Gene Expression Core Facility.

Why did you choose EPFL?

I applied to a variety of places but what EPFL offers as infrastructure for beginning scientists is amazing. When I worked at the Memorial Sloan Kettering Cancer Center it was only cancer and all the labs were thinking in the same way; and that blocks creativity. Whereas here you have such diverse groups who work on the same problems but come at it completely differently, and that makes me very enthusiastic because we can come at the same problems from so many angles and ask these questions and find better solutions. That is one thing that really attracted me to EPFL. There are only few places in the world where you have such a high-level technology side in a life science school that come together. For that, EPFL is just really cool.

The environment is just is also amazing here; you can’t beat that. The people here are just top-notch. If you ask people, e.g. in the US, if they know one place for cancer research in Europe, they know ISREC. They know this place and they think it's really great.

Finally, the international appeal of EPFL is very important for me. I love the fact that there are so many different nationalities here. It's very important. I like having different kinds of people, different ways of thinking, different ideas, in the lab – but also around me. It just spurs creativity.

What would you like to achieve while you're here?

Obviously, I want to do good, high-impact science. And what I would really like is that we identify new ways to make prostate cancer treatments more effective or make new treatments for prostate cancer that is resistant to conventional anti-androgen drugs. I like these concepts of cancer of how the tumor evolves, and I would really like to see if we can apply this to different types of cancer. So, we are also working a little on mammary and endometrium cancers.

We also want to make a new organoid platform as well, and there is a person currently training in my lab with all the organoid techniques. She worked with yeast, so she had very little cell culture experience. But she will be an organoid expert as well!

Karthaus lab