Language

English

Publication Date

4-1-2026

Journal

Nature

DOI

10.1038/s41586-026-10264-6

PMID

41882358

PMCID

PMC13083265

PubMedCentral® Posted Date

3-25-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Posterior fossa type A (PFA) ependymoma is an unusual infantile brain tumour with few known somatic mutations, thought to be driven by epigenetic mechanisms1. PFA ependymoma has a markedly higher incidence and worse prognosis in male children than in female children2. The mechanisms that underlie these sex differences are at present unknown. Here we show that the cellular hierarchy of PFA ependymoma is less differentiated in male individuals than it is in female individuals. In the normal developing mouse hindbrain, male gliogenic progenitors are less differentiated than matched female sibling controls. To further parse the effects of chromosomal versus gonadal contributions in the male hindbrain, we used the four-core genotype mouse model3, which showed that androgen signalling, rather than sex chromosomes, prolongs hindbrain differentiation in male mice. Androgen supplementation promotes the growth of PFA ependymoma, but not that of other brain tumours. Conversely, androgen blockade diminishes both the stem-like potential and the proliferation of PFA ependymoma. We conclude that androgen signalling in both the normal developing hindbrain and PFA ependymoma is sufficient to promote growth and delay differentiation. Anti-androgen therapies represent a potential clinical avenue to target this currently untreatable childhood cancer.

Keywords

Animals, Female, Humans, Male, Mice, Androgen Antagonists, Androgens, Brain Neoplasms, Cell Differentiation, Cell Proliferation, Disease Models, Animal, Ependymoma, Receptors, Androgen, Rhombencephalon, Sex Characteristics, Signal Transduction, CNS cancer, Cancer stem cells, Paediatric cancer, Glial progenitors, Cancer genomics

Published Open-Access

yes

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