Spotlight on Zebrafish in Translational Research
Spotlight on Zebrafish in Translational Research
By Yevgenya Grinblatt, Professor, Dept. of Neuroscience, University of Wisconsin
and Pascale Bomont, Professor & ERC group leader in Cell Biology/Neurosciences, University of Lyon.
Zebrafish researchers around the world are thinking beyond using the zebrafish to address fundamental questions in developmental biology, and even beyond using zebrafish models to understand the basis of human genetic disease. These researchers are going all the way: using the zebrafish to discover and optimize treatments for human disease. In this issue of the News Splash, we are introducing a new section that highlights the use of zebrafish in translational research. For this inaugural spotlight we spoke with Dr. Rita Fior, Champalimaud Centre for the Unknown, Lisbon, Portugal,about her zebrafish avatar system for the real-time optimization of cancer treatment.
We are here to talk about Z-avatar, the zebrafish xenograft system in which cells from human tumors are transplanted into zebrafish larvae which are then treated with a battery of approved cancer drugs to find out which treatment is the most effective for that particular tumor. Your 2024 Nature Communications paper shows Z-avatars to have remarkable utility for optimizing personalized treatments in colorectal cancer patients. This is very different from the basic developmental genetics focus of your early career in science. Could you tell us about your path from basic to translational research?
I did my Ph. D. on Notch signaling and lateral inhibition in the chick embryo. I was very into developmental biology and a big fan of Julian Lewis, who was working on notch signaling, the segmentation clock, and mathematical modeling – and working with zebrafish. For my postdoc, I worked on clock genes in collaboration with Julian Lewis in the lab of Leonor Saúde in Lisbon. That project didn't go as expected and I ended up studying presomitic mesoderm and establishing another collaboration with Sharon Amacher, a great zebrafish researcher. And that’s how I became a zebrafish developmental biologist.
Midway through my postdoc, in 2009, my mother was diagnosed with lung cancer. At that time, I realized that treatment guidelines had several options with similar response rates, but there was no test to tell which was the best option. So, patients go through rounds of chemo in a trial-and error fashion. This was a wake-up call for me. At a premier oncology hospital in the 21st century, why were they not testing the biopsies to find the best treatment, the way we test for bacteria to choose the right antibiotic, for example?
In 2010, I took the Woods Hole zebrafish course where I learned about Randy Peterson’s small molecule screens. I thought, why don’t we put cancer cells into zebrafish, an in vivo model that is much better than plastic? From that point on, I became a bit obsessed with this idea. So that's how I shifted to cancer research, because I was very annoyed that oncology didn't have a good predictive test for treating patients.
How does your basic science training inform your translational work?
My background in developmental biology strongly biased me to in vivo modeling. To quote from our recent review, when you use plastic or organoids, it is the researcher who is choosing the growth factors and driving the selection, but when you are using the embryo, evolution is doing the selection. I think cancer cells go back in time to undifferentiated embryonic states, and it makes much more sense to study them in an embryonic environment. These last few years, we’ve had amazing results with zebrafish avatars, not just with predicting treatment responses in patients but also with basic cancer biology questions, which is the focus of half of my lab. But 10 years ago, when I first started this project, we had to go back to the drawing board and prove that cancer cells could survive and proliferate in the fish. In the end, two factors turned out to be key to making a robust model: looking at cancer cells at single cell resolution using confocal microscopy and choosing the right injection site.
We have now shown that zAvatars predict treatment outcomes robustly for three cancer types (colorectal, breast and ovarian). We are also using the model to study cancer biology. In our 2021 Nature Comm paper we showed that the zebrafish xenograft host works like a reporter of the state of the tumor microenvironment, which is different for each tumor. Some are more immunogenic, and the fish immune system clears the tumor, but others are more immunosuppressive and block the host’s immune response. We are using zAvatars to understand the biology and to screen for drugs that can boost this innate immune rejection, and I think we're getting there.
What do you see as limitations and next steps?
Having the zAvatar test accepted by the medical community has been a challenge. We have a lot of collaborations with doctors, but they don’t come to us asking for the tests. After reading a book on the history of cystic fibrosis (“Breath from Salt”, by Bijal Trivedi), I thought that a randomized trial was the only way to convince the medical community. We opened the trial this week!
What is your advice for established scientists who may want to take their research into a more translational direction?
The main thing is finding an unmet need. As developmental and cell biologists, we have a lot of skills that can be used to tackle problems in the world that need solving: human disease, veterinary disease and plastic contaminants, to name a few. Our avatar story began when it became clear to me that we needed a predictive test for treatment efficacy before we treated a patient. We also need a test to see if the tumor is completely resistant to known treatments and you want to go off label, or if you sequence the tumor and discover actionable mutations. You also need a test to select patients for clinical trials, so patients don't go into a trial with no benefit or a very reduced benefit. All of these are unmet needs that are still driving our research.
What advice do you have for early-stage trainee scientists who would like to do translational work but stay in zebrafish for the incredible genetics and imaging?
The only advice I have is follow your passion. Whatever you're doing in science, you just need to be passionate about it. And don’t give up, keep going!