Can a tiny fish help us cure cancer?

Zebrafish aren’t flashy like other pet fish.

They lack the flowy fins of bettas and the neon swooshes of tetras. They aren’t safety-cone orange like goldfish or splashed with ink spots like mollies. They’re even outshined by the humble guppy, with its fan-like tail and myriad variations.   

But when Dr. Stephanie Grainger looks at zebrafish, she sees something more.

She sees partners in her quest to cure blood cancers.

“Most people are surprised when I tell them that zebrafish are helping us answer important questions like, ‘how do our blood stem cells form?’” Grainger says. “Blood stem cells are the reason bone marrow transplants are so effective at treating cancers like leukemia or lymphoma. We’re interested in how these cells are made and whether we can translate this knowledge into cures — and zebrafish are helping us do that.”  

Little fish, big impact

Let’s start with the obvious question: why zebrafish?

After all, zebrafish and humans are wildly different. But dig a bit deeper and you’ll find that we have much more in common with these tiny, pinstriped fish than meets the eye, including 70% of our genes.^1,2 That’s right, 70% of the genes that make us human also have counterparts in zebrafish. If you look only at disease-related genes, that figure jumps to 86%.

Once the shock wears off, the similarities start to become clearer. At a fundamental level, humans and zebrafish share the same basic parts: we both have eyes and mouths and skeletons. We have digestive systems and nervous systems helmed by brains. And, importantly for Grainger’s research, we have stem cells, biological blank slates that give rise to all the other cells required to assemble the body.

There also are practical considerations that make them an ideal model for studying health and disease. Zebrafish reproduce quickly and in great numbers. They’re small and get along with other zebrafish, meaning they can be housed together. And, importantly, they develop outside of the womb and are translucent for the first few days of their lives, which allows scientists like Grainger to easily see how their stem cells, tissues and organs develop.

“Zebrafish are really cool,” Grainger says. “They’re ideal for studying how blood stem cells form, how our cells communicate, and how errors in these processes can lead to cancer. Most importantly, they’re helping us figure out how to fix these errors.”   

A game of cellular telephone

Coordinating the activities of the human body’s more than 37 trillion cells falls to complex communication channels called signaling pathways. These biological telephone lines route chemical messages to and from cells, which have specialized receptors on their surface to receive and process signals.  

For Grainger, one of these pathways stands above all others. Called Wnt (and pronounced “wint”), this far-reaching network plays key roles in development and tissue maintenance.

“During development, Wnt is like a manager at a construction site. It directs where everything should go — for example, the head goes on top of the neck while the feet go on the ends of the legs,” she says. “In adults, Wnt helps replenish stem cells and coordinate the resources we need to heal after injury.”

No system is perfect though, she adds. Problems with Wnt contribute to many different diseases, such as osteoporosis, cancer and heart disease.

Scientists have long sought to leverage the Wnt pathway as a target for new cancer treatments, but this task has proven to be immensely difficult. The issue is one of complexity: Wnt comprises many different molecules that interact with each other in wide-ranging ways. Medications that broadly target Wnt can throw the whole pathway into chaos rather than narrowly fixing individual errors.

“It’s like using a sledgehammer when you need a scalpel,” Grainger says. “We’re trying to find the scalpel by understanding how specific members of the pathway interact. This will help us develop highly targeted ways to fix specific problems while leaving the rest of the Wnt pathway alone.”

But how does one detangle such an intricate system?

With zebrafish, of course.

Wnt wins and Frizzled finds

At its core, cancer is a disease of cell division gone wrong. It occurs when malignant cells overpower their own quality control systems and run rampant, greedily leeching vital resources from normal cells and crowding out healthy tissues. Stem cells are no exception and can become cancerous just like other cells.

It gets even thornier from there. Cancers can arise from a vast array of errors. DNA can be damaged. Genes can mutate. Epigenetic marks can be misplaced. Signaling pathways can be disrupted.

All of this happens in zebrafish much the same way it does in humans, which allows Grainger and her team a front row seat to see and analyze these changes in real time.

No single scientist or lab can tackle all of cancer’s roots at once. To make progress, Grainger focuses her efforts on two key players in the Wnt pathway: Wnt9a and Fzd9b (Fzd is pronounced “frizzled”). This pair of signaling molecules interacts to relay messages like, “stop growing!” or “grow more!” to and from cells. For a long time, their relationship has been largely secretive — we just simply didn’t know how they worked together to deliver their information payload.  

But thanks to Grainger and her zebrafish, we now have a much clearer picture. In a recent study published in the prestigious journal Science Signaling, she and her colleagues revealed how Wnt9a and Fzd9b interact to form a molecular complex that is brought into the cell through a process called endocytosis.³

Examining this activity in zebrafish also revealed that Wnt9a-Fzd9b complex is helped along by yet another receptor called EGFR. It’s easy to see why this all is tough to study — there are pathways upon pathways upon pathways, each interacting in unique ways to keep the body up and running.

Grainger’s earlier work detailed how Wnt9a and Fzd9b interact, which in turn helps govern development of blood stem cells in zebrafish. At the time, it was clear that EGFR was an important part of this process, but it wasn’t clear why.  

The new study offers answers. It turns out that EGFR makes slight alterations to Fzd9b, like a tailor tweaking a gown. These small changes kick-start a cascade of reactions that results in Wnt9a-Fzd9b’s grand entrance into the cell, where it delivers messages that support development and tissue maintenance.

This information may seem deep in the weeds, but it could be the key that helps scientists better target medications to specific parts of the Wnt pathway — a potential gamechanger when it comes to developing precision cancer treatments.

Right now, there are no U.S. Food and Drug Administration-approved medications that target Wnt because their effects are too broad. The new findings give scientists a specific target in the Wnt9a-Fzd9b complex, along with an instruction manual for how they interact.

Follow up research is required to confirm their results in cancer cells, but Grainger is hopeful. Medications that target EGFR already exist for other diseases, which could significantly reduce the time needed to translate a lab discovery into actionable treatments.

“We’re thrilled with these findings, which wouldn’t have been possible without zebrafish,” Grainger says. “It’s possible that other molecules in the Wnt and Fzd families interact, which would offer additional potential targets. The sky’s really the limit.”

Authors of the Science Signaling paper include Nicole Nguyen, M.S., Kelsey A. Carpenter, Ph.D., Jessica Ensing, Carla Gilliland, Emma J. Rudisel, Emily M. Mu, Kate E. Thurlow, M.Sc., and Timothy J. Triche, Jr., Ph.D., of Van Andel Institute. VAI’s Optical Imaging Core and Vivarium Core contributed to this work.

Research reported in the Science Signaling paper was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health under award no. R00HL133458 (Grainger); the National Institute of General Medical Sciences of the National Institutes of Health under award no. R35GM142779 (Grainger); the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. R01AI171984 (Triche, Krawczyk and Prokop); the Chan Zuckerberg Initiative DAF, an advised fund of the Silicon Valley Community Foundation, under award no. DAF2022-249404 (Triche); and the Michelle Lunn Hope Foundation (Triche). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders.