A Massachusetts General Hospital research team has developed a new zebrafish model for cancer that could vastly improve our ability to match patients to the right treatments and identify new therapies for cancer.
The model, which was developed by a team led by David Langenau, PhD, and Chuan Yan, PhD from the Langenau Lab in the Department of Pathology and MGH Cancer Center, overcomes many of the previous challenges researchers encountered in modeling cancer in zebrafish larvae.
“We can now witness how an individual cancer cell responds to a drug in a live animal,” says Langenau, who is also an Associate Professor of Pathology at Harvard Medical School and an MGH Research Scholar 2017-2022. “That’s going to be a major step forward for the cancer field.”
Limitations of Existing Models
Zebrafish are small tropical fish that have been used as model organisms for human diseases since the 1960s. They share 70% of their genes with humans and have a similar genetic structure as well as many of the same organ systems.
The fish emerged as a cancer model with the creation of transgenic models of leukemia innovated by Langenau in the early 2000’s, and then latter scientists began engrafting human tumor cells onto two-day-old larvae. While these later models were a major step forward in cancer research, they also came with limitations.
“A real hurdle was that the fish larvae didn’t grow at human temperatures,” Langenau says. “They grow at 34° Celsius (93°F), and we now know that growing human tumors below 37° (98.5°F) affects their cellular behaviors, including responses to therapy.”
Another challenge was that it was only possible to engraft about 50-200 cells into each zebrafish larvae, whereas in mouse models, scientists typically engraft a million cells to form a tumor that more closely resembled a human tumor.
The final issue for the larvae models was that it was difficult to judge the dose of each drug used, because the drug was added to the water the fish were swimming in and there was no away to tell how much the fish ingested.
How These New Models are Different
The new zebrafish models developed in the Langenau Lab are genetically engineered to be immune-comprised, making it easier to engraft tumor cells into adult fish. The fish can also thrive at the average human body temperature and since they are larger in size, drugs can be administered via a small tube in the mouth to ensure more accurate dosing.
Critically, the fish can be engrafted with more tumor cells. “The real innovation that Dr. Chuan Yan came up with was engrafting the tumors into a muscle right below the eye,” Langenau says. “It allows you to engraft about 50,000 tumor cells at any given time.”
Since the fish are optically clear, researchers can then observe tumor cells as they divide and spread through the fish. The cells can also be engineered to express fluorescent proteins to help in tracking specific behaviors including therapy responses.
An Early Success in Identifying New Treatments
Langenau and team have successfully used the new zebrafish models to grow human rhabdomyosarcoma—a muscle cancer that Langenau has been studying for the past 15 years.
By doing so, they have identified a promising new treatment in the form of a combination drug therapy that is already being developed by Astra Zeneca to treat other forms of cancer.
“We found that this combination killed rhabdomyosarcoma cells in live animals and we could use single cell imaging to see how drugs affected the growth rate of these cells,” Langenau says.
The team then replicated their results in mouse models from the lab of Nicholas Dyson, PhD, and Ben Draper, PhD, which was crucial to publishing their findings. They are now working to move the treatment into clinical trials.
“We wouldn’t have been able to do this work any other place than Mass General,” Langenau says. “The confocal imaging, along with state-of-the-art zebrafish facilities, clinical collaborators and research teams like Nick Dyson’s were integral to the team’s success. That doesn’t just happen—it’s because we’re at Mass General.”
MGH Research Scholars Funding Provides Crucial Support
This project received crucial support from Langenau’s 2018 MGH Research Scholar Award. The awards, which are funded by philanthropic donors, provide five years of unrestricted funding ($100K per year for a total of $500K) that can be used to pursue new or unproven areas of research. Dyson is also the James and Shirley Curvey MGH Research Scholar 2012-2017.
“Though we had the money to make the models from the NIH, it really wasn’t allocated for us to go very deeply into cancer applications,” Langenau says. “The MGH Research Scholars Award allowed us to do just that.”