Androgen activity in the male embryonic hindbrain drives lethal PFA ependymoma
Jiao Zhang1,2, Winnie Ong3,4,5, Alexandra Rasnitsyn3,4,6
1Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, TX, USA. jiao.zhang@bcm.edu.
Insights
Androgen signaling drives growth and delays differentiation in infantile Posterior Fossa type A (PFA) ependymoma, particularly in males. Anti-androgen therapies may offer a new treatment for this childhood brain tumor.
Area of Science:
- Pediatric Oncology
- Neuroscience
- Developmental Biology
Background:
- Posterior fossa type A (PFA) ependymoma is a rare infantile brain tumor.
- PFA ependymoma exhibits higher incidence and worse prognosis in males compared to females.
- The underlying mechanisms for these sex-based differences are currently unknown.
Purpose of the Study:
- To investigate the cellular hierarchy and differentiation in PFA ependymoma.
- To elucidate the role of sex chromosomes and gonadal hormones in PFA ependymoma development.
- To explore potential therapeutic targets for PFA ependymoma.
Main Methods:
- Comparative analysis of cellular hierarchy in male and female PFA ependymoma.
- Utilized the four-core genotype mouse model to differentiate chromosomal and gonadal effects.
- Investigated the impact of androgen supplementation and blockade on PFA ependymoma growth and stem-like potential.
Main Results:
- Male PFA ependymoma exhibits a less differentiated cellular hierarchy compared to females.
- Androgen signaling, not sex chromosomes, was found to prolong hindbrain differentiation in males.
- Androgen supplementation promoted PFA ependymoma growth, while blockade diminished stem-like potential and proliferation.
Conclusions:
- Androgen signaling is sufficient to promote growth and delay differentiation in both normal developing hindbrain and PFA ependymoma.
- Targeting androgen signaling with anti-androgen therapies presents a potential therapeutic strategy for PFA ependymoma.
- Understanding the role of androgens opens new avenues for treating this childhood brain cancer.
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.
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