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MEDB-21. SOX2(+) cells: the perpetrators of medulloblastoma relapse

Pediatric brain tumors are the number one cause of cancer-related death in children, with medulloblastoma being the most common type. While survival in patients with medulloblastoma has dramatically improved since chemotherapy was added to standard of care protocols, still 30% of tumors will recur....

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Autores principales: Swiderska-Syn, Marzena, Mir-Pedrol, Julia, Rodriguez-Blanco, Jezabel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165312/
http://dx.doi.org/10.1093/neuonc/noac079.395
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author Swiderska-Syn, Marzena
Mir-Pedrol, Julia
Rodriguez-Blanco, Jezabel
author_facet Swiderska-Syn, Marzena
Mir-Pedrol, Julia
Rodriguez-Blanco, Jezabel
author_sort Swiderska-Syn, Marzena
collection PubMed
description Pediatric brain tumors are the number one cause of cancer-related death in children, with medulloblastoma being the most common type. While survival in patients with medulloblastoma has dramatically improved since chemotherapy was added to standard of care protocols, still 30% of tumors will recur. As recurrent disease in medulloblastoma patients in considered uniformly lethal, it is key to identify the cells allowing tumor relapse, and their targetable regulators. By analyzing single cell transcriptomic data, we uncovered a population of SOX2 labeled astrocyte like cells resistant to SMO inhibitors in clinical trials. Using SOX2-enriched medulloblastoma cultures, we observed that SOX2(+) cells rely on non-canonical GLI signaling to propagate medulloblastoma. Therefore, in vivo inhibition of SHH signaling using functionally different GLI inhibitors depleted the SOX2(+) cell pool, what led to less aggressive tumors that lacked the ability to further engraft. Stressing the translational relevance of our findings, a clinically relevant GLI inhibitor not only exhausted SOX2(+) cells driving tumor relapse, but increased overall survival in mice harboring medulloblastoma. Our results emphasize the importance of using targeted therapies that deplete SOX2(+) cells to prevent medulloblastoma recurrence.
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spelling pubmed-91653122022-06-06 MEDB-21. SOX2(+) cells: the perpetrators of medulloblastoma relapse Swiderska-Syn, Marzena Mir-Pedrol, Julia Rodriguez-Blanco, Jezabel Neuro Oncol Medulloblastoma Pediatric brain tumors are the number one cause of cancer-related death in children, with medulloblastoma being the most common type. While survival in patients with medulloblastoma has dramatically improved since chemotherapy was added to standard of care protocols, still 30% of tumors will recur. As recurrent disease in medulloblastoma patients in considered uniformly lethal, it is key to identify the cells allowing tumor relapse, and their targetable regulators. By analyzing single cell transcriptomic data, we uncovered a population of SOX2 labeled astrocyte like cells resistant to SMO inhibitors in clinical trials. Using SOX2-enriched medulloblastoma cultures, we observed that SOX2(+) cells rely on non-canonical GLI signaling to propagate medulloblastoma. Therefore, in vivo inhibition of SHH signaling using functionally different GLI inhibitors depleted the SOX2(+) cell pool, what led to less aggressive tumors that lacked the ability to further engraft. Stressing the translational relevance of our findings, a clinically relevant GLI inhibitor not only exhausted SOX2(+) cells driving tumor relapse, but increased overall survival in mice harboring medulloblastoma. Our results emphasize the importance of using targeted therapies that deplete SOX2(+) cells to prevent medulloblastoma recurrence. Oxford University Press 2022-06-03 /pmc/articles/PMC9165312/ http://dx.doi.org/10.1093/neuonc/noac079.395 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Medulloblastoma
Swiderska-Syn, Marzena
Mir-Pedrol, Julia
Rodriguez-Blanco, Jezabel
MEDB-21. SOX2(+) cells: the perpetrators of medulloblastoma relapse
title MEDB-21. SOX2(+) cells: the perpetrators of medulloblastoma relapse
title_full MEDB-21. SOX2(+) cells: the perpetrators of medulloblastoma relapse
title_fullStr MEDB-21. SOX2(+) cells: the perpetrators of medulloblastoma relapse
title_full_unstemmed MEDB-21. SOX2(+) cells: the perpetrators of medulloblastoma relapse
title_short MEDB-21. SOX2(+) cells: the perpetrators of medulloblastoma relapse
title_sort medb-21. sox2(+) cells: the perpetrators of medulloblastoma relapse
topic Medulloblastoma
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165312/
http://dx.doi.org/10.1093/neuonc/noac079.395
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