Obliteride Impact: Cecilia Moens and the Zebrafish

Each year, Obliteriders commit to raising big dollars to help Fred Hutch cure cancer faster. In 2017, Obliteriders came together to raise over $2.8 million, our largest fundraising year yet. Every one of these Obliterider-raised dollars goes to funding research at the Hutch.

To learn how these funds are advancing the Hutch’s work, the Obliteride team is visiting recipients of the funds and learning about their research. Let’s meet Dr. Cecilia Moens, one of the 2017 Obliterider Powered Researchers. Moens and her laboratory team in the Hutch’s Basic Sciences Division study the zebrafish to better understand the human brain.

Tiny zebrafish and the human brain
MoensWhen Dr. Cecilia Moens reflects on her decades of research uncovering the genes and proteins that craft and shape the brain, she likes to give credit where credit is due — to the tiny freshwater fish whose unique characteristics make her work possible.

Moens studies zebrafish embryos, which develop outside their mother and are nearly completely transparent, having evolved to hide from predators by looking as much like empty water as a defenseless baby fish can. For Moens that evolutionary adaptation comes with the added bonus that she can watch these junior fish form their brains in real time, peering through their see-through heads.

“I’m a very visual person, as lots of people are,” Moens said. “For me to be able to see the process that I’m interested in studying, looking down a microscope at a living embryo, that makes all the difference.”

Although Moens’ esteem for zebrafish is clear, she’s in it for what the creatures can tell us about our own brains. Many steps in the early stages of zebrafish brain development are, gene by gene, cell by cell, replicated in humans.

“They’re undergoing all those developmental steps that your brain or my brain underwent in the first few weeks of our development,” she said.

By unpicking those steps, Moens and her laboratory team in Fred Hutch’s Basic Sciences Division are discovering not only what makes a human brain tick, but what may go awry in developmental disorders that affect the brain — disorders like autism, spina bifida, or the rarer Joubert and Nance-Horan syndromes.

Although human geneticists identify the mutations that underlie these diseases, developmental research is essential to truly understand the genes, neurons and pathways of molecules that shape each part of the brain. So when biologists find a gene that plays a role in a human disease, there is already a wealth of knowledge about that gene generated by scientists like Moens.

“They’re never starting from ground zero anymore,” Moens said. “What we do as developmental biologists is highly relevant to human developmental disorders.”

What Moens and other developmental biologists study is also relevant to understanding how cancer works, one of the reasons Moens set up her laboratory at Fred Hutch. Many of the things cells do during development — divide rapidly, travel through the body, burrow into new tissue — are replicated when cancer forms, albeit in an incoherent, unorganized fashion.

“Cancer cells are running through a kind of Rolodex of what’s available to [them] for what [they] need to do,” Moens said. “And what cancer cells have available to them are developmental signaling pathways.”

So understanding those pathways means, ultimately, learning more about cancer.

Zebrafish and metastasis
Recently, the research with the zebrafish have provided new insights on the very first stages of metastasis in the skin cancer melanoma.

Led by former Fred Hutch postdoctoral fellow Dr. Minna Roh-Johnson, who recently completed her fellowship in Cecilia Moens Lab, the study revealed that certain migrating immune cells known as macrophages share their internal contents directly with cancer cells — and that cellular mind-meld transfers the immune cells’ ability to migrate through the body to the tumor itself.

It’s long been appreciated that the “tumor microenvironment” and, specifically, the immune cells in and around the tumor, play an important role in many aspects of cancer growth and spread. But this is the first time researchers have observed an immune cell directly and physically contacting and sharing its contents with a tumor cell, Roh-Johnson said. Previous studies had seen macrophages sharing their contents by shedding tiny packages of molecules into their environment, so there seem to be multiple ways of signaling between immune cells and tumor cells, the researchers said.

It’s neither clear what’s being transferred in the exchange nor why it happens. And the team’s laboratory findings don’t yet confirm that these same interactions occur in humans. What is clear is how the contact dramatically changes the tumor cells, the researchers said. The cellular mixing shifts the tumor cells from “meandering” to making a beeline in one direction and — in the fishes’ bodies — hastens cancer metastasis.

In these macrophage-tumor entanglements, which can last for hours, it’s as if the immune cells are teaching the cancer cells how to walk. And they are good teachers.

“Immune cells, they migrate,” said Roh-Johnson. “That’s their function in the body, to actively migrate and look for foreign molecules to eat or attack.”

To examine the role of macrophages in melanoma spread, the researchers used both a mixture of cells in petri dishes as well as human melanoma cells transplanted into zebrafish. Using the see-through fish and fluorescent dyes to label individual cells, the researchers could follow the course of individual melanoma cells as they went from stationary to mobile to spreading through the fish’s body.

Macrophages are a part of our innate immune system, the body’s first line of defense against foreign invaders. But in the context of cancer a switch seems to get flipped, said Moens, who is also one of the study authors.

“We think of macrophages as being good guys, the first responders,” she said. “In the tumor microenvironment, they can have the opposite effect.”

In their zebrafish study, the biologists saw macrophages interacting extensively with melanoma cells. Even though these immune cells are “very dynamic,” Roh-Johnson said, those cell-to-cell contacts were extensive, lasting upward of nine hours.

 

Investment in Basic Sciences
As a comprehensive cancer center, Fred Hutch adheres to the ideal of supporting fundamental research alongside all the other areas of cancer research. The work being done in our Basic Sciences Division provides insights to researchers all over the world. Moens’ work with zebrafish can lead to breakthroughs in cancer research right here at home, and it can also inspire new approaches and experiments in labs across the globe. Unrestricted funding, such as the funds from Obliteride, provides support for postdoctoral fellows, like Roh-Johnson, as well as the freedom for future experimentation for the Moens Lab.

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