Most cancers are driven by genetic changes that help cancer cells grow out of control. Those unusual changes often help physicians characterize a disease and, in some cases, guide personalized treatments. But not all cancers follow this pattern. Some show remarkably few genetic mutations — leaving researchers with limited clues about what drives the disease or how best to treat it.
That challenge has shaped years of research into posterior fossa type A (PFA) ependymoma, an aggressive brain tumor that affects infants and very young children. With no effective chemotherapy, treatment relies largely on surgery and radiation — approaches that can have lasting effects on children’s developing brains and highlight the need for more targeted options.
Clinicians have also observed a striking pattern: PFA ependymoma occurs more often in boys, who also tend to have worse outcomes than girls.
A new study published in Nature offers an explanation. An international team of researchers, co-led by Antony Michealraj, Ph.D., assistant professor of neurological surgery at the University of Pittsburgh School of Medicine and a corresponding author on the paper, found that PFA ependymoma is not driven by genetic mutations, but by androgen signaling — hormones that play a normal role in early brain development.
“This tumor is much more common in boys than in girls, and that difference appears very early in life,” Michealraj said. “What we found is that androgen activity during early brain development enriches the very cells that later give rise to this tumor.”
Because PFA ependymoma lacks the mutations that typically drive cancer, researchers suspected a different biological mechanism was at work. The study sets out to answer two key questions: What drives PFA ependymoma if not genetics? And why does the disease affect boys more often — and more severely?
The answers point to androgens, a group of hormones that include testosterone. During early brain development, androgens help ensure that certain brain stem cells — the early “starter” cells that later mature into specialized brain cells — continue dividing long enough for normal growth. Under typical developmental conditions, this temporary delay in maturation is beneficial. In PFA ependymoma, Michealraj said, “we found that the androgen activity during early brain development was enriching the very cells that later give rise to this tumor, creating conditions that may allow cancer to form and progress.”
Using mouse models and laboratory studies, the researchers found that cells in the hindbrain — the region where PFA ependymomas arise — continue to divide for longer periods instead of becoming specialized brain cells, making them more vulnerable to becoming cancerous. The researchers showed that this delayed maturation is linked to higher cancer risk and more aggressive disease.
Importantly, they demonstrated that this difference is driven by hormone signaling rather than sex chromosomes — meaning it is not the XX or XY genetic makeup that matters, but exposure to androgens during early development. As a result, PFA ependymoma is not simply a “male tumor,” but rather a tumor that is responsive to androgen signaling.
When androgen signaling was blocked in mouse models and laboratory experiments, tumor growth slowed, stem-like cell populations decreased and overall cell proliferation was reduced. These effects were not observed in other pediatric brain tumors, highlighting the specificity of the response.
The researchers emphasize that this work represents an early step, as the findings are based on preclinical models, including mice and patient-derived tumor cells studied in the laboratory. The team will continue their research at UPMC Children’s Hospital of Pittsburgh, using patient-derived models to better understand the underlying mechanisms of this pediatric brain cancer and to provide a biological foundation that could guide future research and inform carefully designed clinical studies.
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