Christian Mosimann and Alexa Burger didn’t set out to become chordoma researchers.
The Swiss husband-and-wife team were introduced to chordoma during their postdoctoral stints in Boston at the Harvard Medical School, where Mosimann, a molecular biologist and geneticist, was conducting research at Boston Children’s Hospital and Burger, a cancer biologist, worked on pediatric cancer at Massachusetts General Hospital (MGH). There, the duo, who had previously performed research using fruit flies and mice, became interested in the emerging approach of using zebrafish as a model for human cancers.
“Zebrafish, in addition to developing similar to humans initially as embryo, are also easy to handle and take up less space than mice, so researchers can do experiments rapidly and at larger scales,” Mosimann explains. “We can use these beautiful animals to mimic what’s going on in human patients and learn how tumors develop so clinicians can use this information to develop targeted treatments.”
As part of her research at MGH, Burger attempted to introduce different genetic changes into zebrafish that were commonly seen in epithelial cancers in hopes of coaxing similar tumors to develop in the fish. A couple of days after one such experiment in 2012, Burger returned to find many of her fish with tumors not in their gut but rather arising from the developing spine of the fish. Puzzled at first, she eventually figured out that the genetic changes she introduced had inadvertently been directed at the developing notochord – the embryonic tissue from which chordoma is derived – and that the tumors she was observing looked a lot like human chordomas.
At that point, scientists had been trying for several years to develop a zebrafish model of chordoma which could be used for drug screening experiments. Burger knew she was on to something when a drug that has been used to treat chordoma – rapamycin – slowed the growth of the tumors in her fish.
Zebrafish could be a particularly good model for chordoma, Burger explains, because the notochord is easily visible in the embryos. “We can even genetically insert a glowing protein into the zebrafish notochord so that, when we put it under a microscope and ultraviolet light, we can actually observe the notochord developing. Then, if we induce chordoma in the zebrafish, and we can watch how normal cells turn into chordoma cells.”
But while Burger’s fish appeared to have chordoma, one problem remained: the exact genetic change that caused the zebrafish tumors, namely activating mutations in the Ras oncogene, hadn’t been reported in human chordoma tumors. Nonetheless, the formation of chordoma in zebrafish by perturbing of the Ras pathway mimics the downstream effect that several genetic alterations found in human chordoma are predicted to cause. Most importantly, this discovery paired with the versatile genetic tools in zebrafish set the stage to dig deeper.
In 2013, the couple returned to the University of Zürich’s Institute of Molecular Life Sciences to continue this research in the framework of their zebrafish lab’s genetic studies on molecular mechanisms of development. Having already discovered how to genetically engineer cells in the zebrafish notochord, they set out to introduce genetic mutations that are commonly found in human chordoma tumors.
“There are many, many genetic mutations in chordoma cells, most of which we have not been able to causally link to actually causing the tumor – so now, we need to test each individual mutation one by one to figure out which are the ‘smoking guns’ causing chordoma to form,” Mosimann notes. “With this knowledge, we can then go back from the fish tank to the clinicians and inform them about molecules of interest to pursue in chordoma therapy.”
Because chordoma is such a rare disease, and Switzerland is such a small country, Mosimann and Burger are looking beyond Swiss borders for clinical partners in this promising research. They are already collaborating with clinicians at the University Hospital Zürich and experts at Memorial Sloan Kettering Cancer Center in New York, but they hope to build a bigger international network of collaborators. As researchers discover new genetic changes in chordoma tumors, Mosimann and Burger hope to be able to quickly introduce them into zebrafish to see if they are sufficient and necessary for forming chordoma tumors. If tumors form, they can be used for drug testing, which could potentially inform treatment for chordoma patients with the same genetic changes in their tumors.
“Then, we can give this information to our collaborators in the clinic, who can apply this learning to treat their patients,” says Mosimann.
Contributing to building that network, in July 2016 Burger and Gianluca D’Agati, a graduate student in their lab, presented their findings at the Chordoma Foundation’s Fifth International Chordoma Research Workshop in Boston. That experience helped the team meet new collaborators, learn about other research, and generate new ideas for how their model can help advance chordoma research.
“As scientists working in the lab, this conference was extremely inspiring because it provided the perfect opportunity to connect with physicians and surgeons on the front lines of treating chordoma,” says Burger.
The team’s innovative approaches of combining clinical input with basic research in the zebrafish model to catch new molecular mechanisms of chordoma formation resonate widely in the community. In October 2016, Mosimann and Burger received a multi-year research grant from the Swiss Bridge Foundation. Of this grant, Mosimann says, “We feel especially honored as we are the very first zebrafish researchers to receive this prestigious award. We hope this will provide visibility to rare cancer research, including chordoma, and to the use of model organisms as a powerful bridge between basic and clinical research.”
Now, as Mosimann and Burger work to perfect their model, they are reaching out to the other researchers who want to join forces. “We’re excited to develop partnerships so we can hopefully make an even bigger splash.”
Drs. Mosimann and Burger would love to talk with other researchers and clinicians about collaborating. If interested, please reach out to them at email@example.com or firstname.lastname@example.org.
To learn more about zebrafish and their importance in scientific research, click here.