Mayo Clinic researchers show how neuroblastoma spreads

Volume 6, Issue 4, 2017


A zebrafish model uncovers the dysregulation of genes associated with the extracellular matrix.

Shizhen (Jane) Zhu, M.D., Ph.D.

Shizhen (Jane) Zhu, M.D., Ph.D.

For the first time, Mayo Clinic researchers and their colleagues from other institutions have demonstrated how nervous system tumors called neuroblastomas spread.

Their findings clarify the relationship between two genes that fuel the aggressive spread of neuroblastomas. The results of their research were published Sept. 11, 2017, in Cancer Cell.

Neuroblastoma is a cancer that most commonly affects children age 5 and younger, rarely occurring in older children. Neuroblastoma develops from immature nerve cells found in several areas of the body, usually arising in and around the adrenal glands, which have similar origins to nerve cells and sit atop the kidneys. Neuroblastoma characteristics are linked to genetic alterations.

"Increased expression of the LMO1 gene is associated with aggressive, high-risk neuroblastomas," said Shizhen (Jane) Zhu, M.D., Ph.D., lead author of the Cancer Cell paper and a Mayo Clinic biomedical researcher in Rochester, Minnesota. "Our genetic analyses using zebrafish demonstrate for the first time that LMO1 cooperates with the MYCN gene to accelerate tumor onset and increase tumor penetrance."

Two strains of zebrafish, developed at Mayo Clinic's Zebrafish Facility, were engineered to express either LMO1 or MYCN at high levels. Zebrafish allow scientists to examine genetic changes associated with certain diseases, including neuroblastoma.

"We developed the first zebrafish model of neuroblastoma metastasis to uncover the molecular mechanism underlying LMO1-mediated neuroblastoma spread, because this is a major problem in two-thirds of the children who have high-risk disease at diagnosis," Dr. Zhu said.

As the authors report in the Cancer Cell paper, the two strains of zebrafish were interbred. In the fish expressing both MYCN and LMO1, the authors observed tumor development in 80 percent of the offspring by 24 weeks of age. In offspring expressing only the MYCN gene, tumors developed in only 20 to 30 percent during the same time period.

"This is the first evidence in an animal model that high levels of LMO1 expression promote metastasis of MYCN-induced neuroblastoma," Dr. Zhu said. "The mechanism to account for this, according to our findings, is the dysregulation of genes associated with the extracellular matrix."

The extracellular matrix is the material between cells. It includes structural and chemical elements that link cells physically and by communication. In zebrafish expressing both genes, markers of stiffness increased in the extracellular matrix. The authors suggest that a high level of LMO1 expression changes expression of genes controlling the extracellular matrix. And that, in turn, may lead to alterations that benefit tumor growth and spread.

"Knowing how LMO1 contributes to neuroblastoma aggression does not directly apply to patients today," Dr. Zhu said. But she emphasizes that this zebrafish model is vital to address the unmet needs of patients in the future.

"Our zebrafish model of neuroblastoma with transgenic expression of LMO1 and MYCN should provide a valuable platform for evaluating the effects of drugs to prevent or inhibit neuroblastoma metastasis going forward," Dr. Zhu said. Her laboratory is conducting follow-up studies based on the unique zebrafish model from this study to translate the knowledge into effective therapies.