Model developed by HSCI researchers enables visualization of drug response
The goal of personalized cancer therapy is to know which drugs will work on a patient’s specific tumor before treatment starts. In a step toward this goal, Harvard Stem Cell Institute (HSCI) scientists have developed a zebrafish model of cancer that could be less expensive than existing approaches, and can be used to visualize drug responses at a single-cell resolution in live animals. The researchers used it to identify a promising new treatment for rhabdomyosarcoma, a muscle cancer that primarily affects children.
“We have created the first immune-compromised zebrafish model that can robustly engraft and grow human cancers,” said David Langenau, Ph.D., HSCI Principal Faculty member and senior author of the study, published in Cell. Langenau is an associate professor of pathology at Harvard Medical School and Massachusetts General Hospital.
Chuan Yan, Ph.D., a postdoctoral fellow in Langenau's lab and first author of the study, said, “These immune-compromised zebrafish are optically clear, allowing us to visualize cellular characteristics and therapeutic responses of single cancer cells over time. The model has the potential to transform the scale of personalized therapy and, for the first time, provides unprecedented ability to image a variety of cancer processes at single-cell resolution.”
Developing the zebrafish model
By transplanting human cancer cells into animal models, researchers have been able to study tumor growth, metastasis, and drug response. But traditional mouse models have significant limitations, including the cost and space required to maintain them, and the difficulty in visualizing tumor cells implanted beneath the animals’ fur-covered skin.
In previous studies, scientists implanted human tumor cells into two-day-old zebrafish larvae that had not yet developed immune systems. But the implants were eventually rejected by the immune system, so scientists could not study the cells’ response to drugs over a long period of time.
Langenau’s team overcame these hurdles by developing a mutant zebrafish strain with two key features:
- It was transparent, so the researchers could see the implanted cancer cells, track their growth, and observe how drugs affected the tumors.
- It had mutations in two genes, so the animals lacked the key cells of the immune system.
Searching for cancer drugs
The team used the new model to investigate whether a combination of two drugs — olaparib and temozolomide, which are currently in a clinical trial for Ewing’s sarcoma — could inhibit rhabdomyosarcoma growth.
Their experiments using both the new zebrafish model and mouse models showed that, while treatment with either drug alone had limited effectiveness against either cancer, the combination treatment eliminated rhabdomyosarcoma cells from both types of animal models.
“The work is particularly exciting for two reasons,” said Langenau. “First, we identified a potential new therapy for a devastating childhood cancer. Second, we now show that a wide variety of human tumors can grow in immune-deficient zebrafish. The model has the potential to change how we assess drugs prior to moving into the clinical setting — reducing the cost and time required, allowing rapid assessment of combination therapies, and directly visualizing drug responses at single-cell resolution. The model will be truly transformative for cancer biology.”
Bringing treatment to the clinic
The researchers are now working with clinical teams at Massachusetts General Hospital and Dana-Farber Cancer Institute, along with the involved pharmaceutical companies, to refine the existing clinical trial to include rhabdomyosarcoma. Langenau’s team is also exploring potential uses for the model in immunotherapy, stem cell biology, and regenerative medicine.
Support for the study includes National Institutes of Health grants R24 OD016761, R01 CA154923, R01 CA215118, R01 CA211734 and R01 CA226926; and grants from the Alex’s Lemonade Stand Foundation, the Liddy Shriver Sarcoma Initiative, and the MGH Research Scholars Program.
The Massachusetts General Hospital has a patent pending for the work described in this paper.
Source article: Yan, C. et al. (2019). Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish. Cell. https://doi.org/10.1016/j.cell.2019.04.004
The original version of this story was published on the Massachusetts General Hospital website on April 25, 2019.