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

Jamie Zagozewski, Ghazaleh M. Shahriary, Ludivine Coudière Morrison, Olivier Saulnier, Margaret Stromecki, Agnes Fresnoza, Gareth Palidwor, Christopher J. Porter, Antoine Forget, Olivier Ayrault, Cynthia Hawkins, Jennifer A. Chan, Maria C. Vladoiu, Lakshmikirupa Sundaresan, Janilyn Arsenio, Michael D. Taylor, Vijay Ramaswamy and Tamra E. Werbowetski-Ogilvie ()
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Jamie Zagozewski: University of Manitoba
Ghazaleh M. Shahriary: University of Manitoba
Ludivine Coudière Morrison: University of Manitoba
Olivier Saulnier: 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
Olivier Ayrault: PSL Research University, CNRS UMR, INSERM
Cynthia Hawkins: The Hospital for Sick Children
Jennifer A. Chan: University of Calgary
Maria C. Vladoiu: The Hospital for Sick Children
Lakshmikirupa Sundaresan: The Hospital for Sick Children
Janilyn Arsenio: Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba
Michael D. Taylor: The Hospital for Sick Children
Vijay Ramaswamy: The Hospital for Sick Children
Tamra E. Werbowetski-Ogilvie: University of Manitoba

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17357-4

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DOI: 10.1038/s41467-020-17357-4

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