ZR fusion protein sways normal brain cell development toward cancer growth

HOUSTON – (March 25, 2026) – Researchers at Texas Children’s Hospital and Baylor College of Medicine, in collaboration with colleagues at St. Jude Children’s Research Hospital and other institutions, report in Nature a newly identified mechanism driving the development of pediatric supratentorial ependymoma (EPN), the third most common brain tumor in children. The findings point to promising new strategies for treating these aggressive and chemotherapy-resistant tumors.

“Pediatric brain tumors are often thought to originate early during brain development, but what drives the transformation of normal developing brain cells into cancer cells is still not fully understood,” said first author Alisha Kardian, a graduate student in Baylor’s Cancer and Cell Biology Graduate Program who conducted this work in collaboration with investigators at Texas Children’s. “We discovered a mechanism that harnesses normal brain development processes to fuel tumor growth.”

The team focused on one of the most common forms of pediatric ependymoma, known as ZFTA-RELA (ZR) fusion-positive ependymoma. ZR ependymomas arise almost exclusively in the brain cortex of young children. These tumors are caused by the fusion of two genes—ZFTA and RELA—creating an abnormal protein that activates cancer-promoting genes.

Despite this understanding, a key question has remained: why this fusion protein drives tumor formation only during early childhood and within specific cell types. “We reasoned that the answer might lie in the developmental program of the brain,” Kardian said. “During fetal and early postnatal life, stem-like cells rapidly divide and differentiate into mature cell types, including neurons and glial cells.”

As these cells proliferate, regions of DNA temporarily open, allowing access to genes and creating opportunities for altered gene expression. Once cells mature, however, DNA becomes more tightly packed, limiting that access.

“We found that the ZR fusion protein does not actively open DNA during development,” said co-corresponding author Dr. Stephen Mack of St. Jude Children’s Research Hospital. “Instead, it takes advantage of DNA regions that are already accessible in rapidly dividing cells, altering gene expression in ways that promote tumor formation.”

Further studies revealed that once ZR activates this process, a dominant cancer ‘founder’ clone emerges, generating a diverse tumor that partially mirrors normal brain development but remains locked in an immature state.

“Understanding these developmental vulnerabilities is critical,” said co-corresponding author Dr. Benjamin Deneen, principal investigator at Texas Children’s Jan and Dan Duncan Neurological Research Institute and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “These insights open the door to new therapeutic strategies aimed at pushing tumor cells toward full maturation or targeting the early progenitor cells that sustain tumor growth.”

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