Androgen activity in the male embryonic hindbrain drives lethal PFA ependymoma

  • Nature. 2026 Apr;652(8110):763-773. doi: 10.1038/s41586-026-10264-6.
Jiao Zhang  #  1  2 ,  Winnie Ong  #  3  4  5 ,  Alexandra Rasnitsyn  #  3  4  6 ,  Ricardo Daniel Gonzalez  7  8 ,  Rodrigo Lopez Gutierrez  9  10 ,  Polina Balin  7  8 ,  Amr Saadeldin  7  8  11 ,  Xiaochong Wu  7  8 ,  Maria C Vladoiu  3  4  5 ,  Vicente Santa-Maria Lopez  7  8 ,  Fernando Gonzalez-Salinas  7  8 ,  Navneesh Yadav  12 ,  Dinesh Mohanakrishnan  12 ,  Kannan Boosi Narayana Rao  12 ,  Raja Gopal Reddy Mooli  13 ,  Hinda Najem  14 ,  Sebastian Pacheco  14 ,  Kaitlin Kharas  3  4  5 ,  Cory Richman  3  4  6 ,  David Przelicki  3  4  5 ,  Evan Y Wang  3  4  6 ,  Haipeng Su  7  8 ,  Rachel Naomi Curry  7  8 ,  Runze Yang  15 ,  Michelle Masayo Kameda-Smith  7  8 ,  Bryn Livingston  3  4  5 ,  David Scott  3  4 ,  Zaili Luo  16 ,  Mingyang Xia  17 ,  Namal Abeysundara  3  4 ,  Anders W Erickson  3  4  5 ,  Ncedile Mankahla  5  18 ,  Lucas ZhongMing Hu  19 ,  Chu Pan  20 ,  Raul Suarez  3  4 ,  Ning Huang  7  8 ,  Yihao Wu  7  8 ,  Hao Wang  3  4 ,  Tajana Douglas  3  4 ,  Jonelle Pallota  3  4 ,  Steven Hébert  9  10 ,  Karen Ng  20 ,  Krystin Mantione  21 ,  Heather Whetstone  3  4 ,  Hassaan Maan  6  22  23 ,  Hussein Lakkis  9  10 ,  Juyeun Lee  24  25 ,  Sadeesh K Ramakrishnan  13 ,  Yanxin Pei  26  27 ,  Yujie Tang  28 ,  Frank Y Lin  7  8  29 ,  Guillermo Aldave  30  31 ,  Marco Gallo  7  8  29 ,  Robert M Friedlander  12 ,  Faiyaz Notta  4  20 ,  Laura K Donovan  3  4 ,  Murali Chintagumpala  7  8 ,  Bo Wang  5  22  23  32 ,  Yun Li  4  33 ,  Daniel D De Carvalho  6  20 ,  Zhaolei Zhang  32  33  34 ,  Ying Mao  35  36 ,  Wei Hua  35  36 ,  Charles Eberhart  37 ,  Calixto-Hope G Lucas  37 ,  Sriram Venneti  38 ,  Poul H Sorensen  39 ,  Alberto Delaidelli  39  40 ,  Hao Li  41 ,  Wenhao Zhou  42 ,  Jason Kirk  21 ,  Dean G Tang  21 ,  Tao Jiang  43  44 ,  Hailong Liu  45  46  47  48 ,  Justin D Lathia  24  25 ,  Hiromichi Suzuki  49 ,  Jeremy N Rich  50 ,  Lincoln D Stein  33  51 ,  Nada Jabado  9  52  53 ,  Vijay Ramaswamy  3  4  6  54 ,  Q Richard Lu  55 ,  Amy B Heimberger  14 ,  Craig Daniels  7  8 ,  Kulandaimanuvel Antony Michealraj  56  57 ,  Claudia L Kleinman  58  59 ,  Michael D Taylor  60  61  62  63  64  65  66  67  68  69
Affiliations
  • 1. Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, TX, USA. [email protected].
  • 2. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 3. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 4. Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 6. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 7. Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, TX, USA.
  • 8. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA.
  • 9. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • 10. Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada.
  • 11. Development, Disease Models and Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, USA.
  • 12. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 13. Division of Metabolism and Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 14. Department of Neurological Surgery, Northwestern University, Chicago, IL, USA.
  • 15. Section of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
  • 16. Department of Pediatrics, Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 17. Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
  • 18. Department of Neurosurgery, St Michael's Hospital, Toronto, Ontario, Canada.
  • 19. Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.
  • 20. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 21. Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 22. Vector Institute, Toronto, Ontario, Canada.
  • 23. Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
  • 24. Case Comprehensive Cancer Center, Cleveland, OH, USA.
  • 25. Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 26. Center for Cancer and Immunology, Brain Tumor Institute, Children's National Hospital, Washington, DC, USA.
  • 27. Department of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
  • 28. Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 29. The Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 30. Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA.
  • 31. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
  • 32. Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
  • 33. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 34. Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
  • 35. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
  • 36. National Center for Neurological Disorders, Shanghai, China.
  • 37. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
  • 38. Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 39. Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
  • 40. Department of Pathology, Mass General Brigham, Harvard Medical School, Boston, MA, USA.
  • 41. Department of Neurosurgery, Children's Hospital of Fudan University, Shanghai, China.
  • 42. Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 43. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 44. Department of Neurosurgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
  • 45. China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 46. Beijing Neurosurgical Institute, Beijing, China.
  • 47. Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 48. Chinese Institute for Medical Research, Beijing, China.
  • 49. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
  • 50. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 51. Adaptive Oncology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 52. Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
  • 53. Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
  • 54. Division of Haematology and Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 55. Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 56. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
  • 57. Cancer Biology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. [email protected].
  • 58. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [email protected].
  • 59. Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada. [email protected].
  • 60. Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, TX, USA. [email protected].
  • 61. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 62. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [email protected].
  • 63. Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada. [email protected].
  • 64. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 65. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 66. The Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 67. Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA. [email protected].
  • 68. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 69. Department of Surgery, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • # Contributed equally.
PMID: 41882358 DOI: 10.1038/s41586-026-10264-6
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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