Zebrafish model explains how recurring cancer may resist treatment

Zebrafish Zebra Barb Danio rerio freshwater aquarium fish

UT Health San Antonio researchers are learning how stem cell biology causes 30 percent of children who have a rare muscle cancer to relapse and not respond to treatment.

To do this, the lab of Myron Ignatius, Ph.D., at UT Health’s Greehey Children’s Cancer Research Institute, is using zebrafish. These fish have the unusual trait of being translucent. “Zebrafish are like a glass of water. You can see right through them,” said Dr. Ignatius, assistant professor of molecular medicine at UT Health.

He is first author of a study published in Cell Reports that shows how two signaling pathways work together to establish treatment-resistant secondary tumors that are biologically different from the original tumor.

Rhabdomyosarcoma is a major soft tissue tumor seen in children. Dr. Ignatius’ lab has been able to see secondary rhabdomyosarcoma tumors form in living fish. By labeling cell types with colors, they track the progression of stem cells into immature cancer cells and then into mature cancer cells.

Stem cells are prolific and have the versatility to become any type of cell. They also are the only cells that can duplicate themselves. It is thought that only cancer stem cells can make the other types of tumor cells. Stem cells also are the cells most likely to survive cancer treatments and give rise to secondary tumors, Dr. Ignatius said.

In the Cell Reports paper, Dr. Ignatius and his colleagues found that in rhabdomyosarcoma tumors, cancer stem cells can also be produced by immature cancer cells. Essentially, two signaling pathways, NOTCH1 and RAS, collaborate to cause the immature cancer cells to go back a developmental step to become stem cells, where they proliferate to form the new tumors.

“This is very surprising,” Dr. Ignatius said. “The ability to move back a developmental step results in a greater than 20-fold increase in cancer stem cells in the tumors. This is the first time that this phenomenon has been observed in rhabdomyosarcoma.

“And this explains how NOTCH1-expressing tumors can change their biology and become more difficult to treat,” he added.

The researchers confirmed their findings in cells grown in culture and with tumor samples from patients.

Having defined important pathways that impact tumor growth through this study, Dr. Ignatius is now testing whether inhibiting the NOTCH1 pathway will help patients better fight the disease.

Dr. Ignatius was recruited to UT Health San Antonio in the fall of 2016 with a $2 million Cancer Prevention & Research Institute of Texas (CPRIT) grant. He brought the zebrafish model to UT Health from Massachusetts General Hospital/Harvard Medical School, where he previously worked and where he helped develop the zebrafish model in collaboration with his former mentor, David M. Langenau, Ph.D.

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