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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate

Author

Listed:
  • Jamie Zagozewski

    (University of Manitoba)

  • Ghazaleh M. Shahriary

    (University of Manitoba)

  • Ludivine Coudière Morrison

    (University of Manitoba)

  • Olivier Saulnier

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Margaret Stromecki

    (University of Manitoba)

  • Agnes Fresnoza

    (University of Manitoba)

  • Gareth Palidwor

    (Ottawa Hospital Research Institute)

  • Christopher J. Porter

    (Ottawa Hospital Research Institute)

  • Antoine Forget

    (PSL Research University, CNRS UMR, INSERM
    Université Paris-Saclay, CNRS UMR 3347, INSERM, U1021)

  • Olivier Ayrault

    (PSL Research University, CNRS UMR, INSERM
    Université Paris-Saclay, CNRS UMR 3347, INSERM, U1021)

  • Cynthia Hawkins

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto)

  • Jennifer A. Chan

    (University of Calgary)

  • Maria C. Vladoiu

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto)

  • Lakshmikirupa Sundaresan

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Janilyn Arsenio

    (Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba
    Manitoba Centre for Proteomics and Systems Biology)

  • Michael D. Taylor

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Vijay Ramaswamy

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto and The Hospital for Sick Children
    University of Toronto)

  • Tamra E. Werbowetski-Ogilvie

    (University of Manitoba)

Abstract

OTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 regulatory network that controls Group 3 medulloblastoma cell fate. OTX2 silencing modulates the repressive chromatin landscape, decreases levels of PRC2 complex genes and increases the expression of neurodevelopmental transcription factors including PAX3 and PAX6. Expression of PAX3 and PAX6 is significantly lower in Group 3 medulloblastoma patients and is correlated with reduced survival, yet only PAX3 inhibits self-renewal in vitro and increases survival in vivo. Single cell RNA sequencing of Group 3 medulloblastoma tumorspheres demonstrates expression of an undifferentiated progenitor program observed in primary tumors and characterized by translation/elongation factor genes. Identification of mTORC1 signaling as a downstream effector of OTX2-PAX3 reveals roles for protein synthesis pathways in regulating Group 3 medulloblastoma pathogenesis.

Suggested Citation

  • Jamie Zagozewski & Ghazaleh M. Shahriary & Ludivine Coudière Morrison & Olivier Saulnier & Margaret Stromecki & Agnes Fresnoza & Gareth Palidwor & Christopher J. Porter & Antoine Forget & Olivier Ayra, 2020. "An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17357-4
    DOI: 10.1038/s41467-020-17357-4
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    Cited by:

    1. Emma Martell & Helgi Kuzmychova & Esha Kaul & Harshal Senthil & Subir Roy Chowdhury & Ludivine Coudière Morrison & Agnes Fresnoza & Jamie Zagozewski & Chitra Venugopal & Chris M. Anderson & Sheila K. , 2023. "Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma," Nature Communications, Nature, vol. 14(1), pages 1-26, December.

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