Jiao Zhang, Winnie Ong, Alexandra Rasnitsyn, Ricardo Daniel Gonzalez, Rodrigo Lopez Gutierrez, Polina Balin, Amr M. Saadeldin, Xiaochong Wu, Maria Vladoiu, Vicente Santa-Maria Lopez, Fernando Gonzalez-Salinas, Navneesh Yadav, Dinesh Mohanakrishnan, Kannan Boosi Narayana Rao, Raja Gopal Reddy Mooli, Hinda Najem, Sebastian Pacheco, Kaitlin Kharas, Cory M. Richman, David Przelicki, Evan Y. Wang, Haipeng Su, Rachel Naomi Curry, Runze Yang, Michelle Masayo Kameda-Smith, Bryn Livingston, David Scott, Zaili Luo, Mingyang Xia, Namal Abeysundara, Anders W. Erickson, Ncedile Mankahla, Lucas ZhongMing Hu, Chu Pan, Raúl A. Suárez, Ning Huang, Yihao Wu, Hao Wang, Tajana Douglas, Jonelle Pallota, Steven Hébert, Karen Ng, Krystin Mantione, Heather Whetstone, Hassaan Maan, Hussein Lakkis, Juyeun Lee, Sadeesh K. Ramakrishnan, Yanxin Pei, Yujie Tang, Frank Y. Lin, Guillermo Aldave, Marco Gallo, Robert M. Friedlander, Faiyaz Notta, Laura K. Donovan, Murali Chintagumpala, Bo Wang, Yun Li, Daniel D. De Carvalho, Zhaolei Zhang, Ying Mao, Wei Hua, Charles G. Eberhart, Calixto-Hope G. Lucas, Sriram Venneti, Poul H. Sorensen, Alberto Delaidelli, Hao Li, Wenhao Zhou, Jason Kirk, Dean G. Tang, Tao Jiang, Hailong Liu, Justin D. Lathia, Hiromichi Suzuki, Jeremy N. Rich, Lincoln D. Stein, Nada Jabado, Vijay Ramaswamy, Q. Richard Lu, Amy B. Heimberger, Craig Daniels, Kulandaimanuvel Antony Michealraj, Claudia L. Kleinman, Michael D. Taylor
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. Androgen activity in the male embryonic hindbrain prolongs hindbrain differentiation in male individuals and drives sex differences in the incidence and prognosis of posterior fossa type A (PFA) ependymoma, an aggressive childhood brain tumour.