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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate
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 medulloblasto...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371715/ https://www.ncbi.nlm.nih.gov/pubmed/32686664 http://dx.doi.org/10.1038/s41467-020-17357-4 |
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author | Zagozewski, Jamie Shahriary, Ghazaleh M. Morrison, Ludivine Coudière Saulnier, Olivier Stromecki, Margaret Fresnoza, Agnes Palidwor, Gareth Porter, Christopher J. Forget, Antoine Ayrault, Olivier Hawkins, Cynthia Chan, Jennifer A. Vladoiu, Maria C. Sundaresan, Lakshmikirupa Arsenio, Janilyn Taylor, Michael D. Ramaswamy, Vijay Werbowetski-Ogilvie, Tamra E. |
author_facet | Zagozewski, Jamie Shahriary, Ghazaleh M. Morrison, Ludivine Coudière Saulnier, Olivier Stromecki, Margaret Fresnoza, Agnes Palidwor, Gareth Porter, Christopher J. Forget, Antoine Ayrault, Olivier Hawkins, Cynthia Chan, Jennifer A. Vladoiu, Maria C. Sundaresan, Lakshmikirupa Arsenio, Janilyn Taylor, Michael D. Ramaswamy, Vijay Werbowetski-Ogilvie, Tamra E. |
author_sort | Zagozewski, Jamie |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7371715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73717152020-07-22 An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate Zagozewski, Jamie Shahriary, Ghazaleh M. Morrison, Ludivine Coudière Saulnier, Olivier Stromecki, Margaret Fresnoza, Agnes Palidwor, Gareth Porter, Christopher J. Forget, Antoine Ayrault, Olivier Hawkins, Cynthia Chan, Jennifer A. Vladoiu, Maria C. Sundaresan, Lakshmikirupa Arsenio, Janilyn Taylor, Michael D. Ramaswamy, Vijay Werbowetski-Ogilvie, Tamra E. Nat Commun Article 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. Nature Publishing Group UK 2020-07-20 /pmc/articles/PMC7371715/ /pubmed/32686664 http://dx.doi.org/10.1038/s41467-020-17357-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zagozewski, Jamie Shahriary, Ghazaleh M. Morrison, Ludivine Coudière Saulnier, Olivier Stromecki, Margaret Fresnoza, Agnes Palidwor, Gareth Porter, Christopher J. Forget, Antoine Ayrault, Olivier Hawkins, Cynthia Chan, Jennifer A. Vladoiu, Maria C. Sundaresan, Lakshmikirupa Arsenio, Janilyn Taylor, Michael D. Ramaswamy, Vijay Werbowetski-Ogilvie, Tamra E. An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate |
title | An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate |
title_full | An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate |
title_fullStr | An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate |
title_full_unstemmed | An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate |
title_short | An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate |
title_sort | otx2-pax3 signaling axis regulates group 3 medulloblastoma cell fate |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371715/ https://www.ncbi.nlm.nih.gov/pubmed/32686664 http://dx.doi.org/10.1038/s41467-020-17357-4 |
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