Scientists discover how brain development programs promote pediatric tumors

A team of researchers from Baylor College of Medicine, St. Jude Children’s Research Hospital, Texas Children’s Hospital and partner institutions revealed in the journal Nature A novel mechanism driving the development of pediatric supratentorial ependymoma (EPN), the third most common pediatric brain tumor. The findings suggest potential new approaches to treating these aggressive and chemo-resistant tumors.

Brain tumors in children are often thought to originate during brain development, but what causes normally developing brain cells to turn into cancer cells is still incompletely understood. “We have discovered a mechanism that acts on normal brain development to promote tumor growth.”

Alisha Kardian, study first author and graduate student, Cancer and Cell Biology Graduate Program, Baylor College of Medicine

The team studied one of the most common types of pediatric ependymomas, known as ZFTA-RELA (ZR) fusion-positive ependymoma. ZR Ependymomas occur almost exclusively in the cerebral cortex of young children, not in other areas of the brain. ZR tumors are caused by a fusion between two genes – ZFTA and RELA – which creates an abnormal protein that can switch on genes that promote cancer.

However, a long-standing mystery has been why this fusion protein causes tumors only during childhood and only in certain types of cells. “We reasoned that the answer may lie in the evolutionary planning of the brain,” Cardian said. “During embryonic and early postnatal life, stem-like cells divide rapidly and eventually give rise to multiple mature cell types, including neurons and glial cells.”

As these cells divide, they expose regions of DNA, opening access to genes and providing the opportunity to change their expression. But once stem cells develop into mature cell types, the DNA locks back into a tight structure.

“We investigated whether the ZR fusion protein had a role in unwinding DNA during embryonic development, but found that ZR does not,” said co-corresponding author Dr. Stephen Mack, associate member of the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital. “Instead, ZR takes advantage of open DNA that is already present in rapidly dividing cells to interact with genetic material and alter its expression in ways that drive tumor generation.”

Further experiments showed that, once activated by ZR, a dominant cancer ‘founder’ clone forms a heterogeneous tumor that partially mimics normal brain development but stops at an immature stage.

“Understanding these developmental vulnerabilities opens the door to new therapeutic approaches aimed at nudging tumor cells toward full differentiation or targeting early progenitor populations that promote tumor growth,” said Dr. Russell J. And Marion K. Blattner Chair, a member of the Dan L. Duncan Comprehensive Cancer Center at Baylor and a principal investigator at Texas Children’s, said the co-corresponding author. Duncan Neurological Research Institute.