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Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence

BACKGROUND: High-intensity therapy effectively treats most TP53 wild-type (TP53-WT) Sonic Hedgehog-subgroup medulloblastomas (SHH-MBs), but often cause long-term deleterious neurotoxicities in children. Recent clinical trials investigating reduction/de-escalation of therapy for TP53-WT SHH-MBs cause...

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Autores principales: Treisman, Daniel M, Li, Yinghua, Pierce, Brianna R, Li, Chaoyang, Chervenak, Andrew P, Tomasek, Gerald J, Lozano, Guillermina, Zheng, Xiaoyan, Kool, Marcel, Zhu, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860004/
https://www.ncbi.nlm.nih.gov/pubmed/31763624
http://dx.doi.org/10.1093/noajnl/vdz027
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author Treisman, Daniel M
Li, Yinghua
Pierce, Brianna R
Li, Chaoyang
Chervenak, Andrew P
Tomasek, Gerald J
Lozano, Guillermina
Zheng, Xiaoyan
Kool, Marcel
Zhu, Yuan
author_facet Treisman, Daniel M
Li, Yinghua
Pierce, Brianna R
Li, Chaoyang
Chervenak, Andrew P
Tomasek, Gerald J
Lozano, Guillermina
Zheng, Xiaoyan
Kool, Marcel
Zhu, Yuan
author_sort Treisman, Daniel M
collection PubMed
description BACKGROUND: High-intensity therapy effectively treats most TP53 wild-type (TP53-WT) Sonic Hedgehog-subgroup medulloblastomas (SHH-MBs), but often cause long-term deleterious neurotoxicities in children. Recent clinical trials investigating reduction/de-escalation of therapy for TP53-WT SHH-MBs caused poor overall survival. Here, we investigated whether reduced levels of p53-pathway activation by low-intensity therapy potentially contribute to diminished therapeutic efficacy. METHODS: Using mouse SHH-MB models with different p53 activities, we investigated therapeutic efficacy by activating p53-mediated cell-cycle arrest versus p53-mediated apoptosis on radiation-induced recurrence. RESULTS: Upon radiation treatment, p53(WT)-mediated apoptosis was sufficient to eliminate all SHH-MB cells, including Sox2(+) cells. The same treatment eliminated most Sox2(−) bulk tumor cells in SHH-MBs harboring p53(R172P), an apoptosis-defective allele with cell-cycle arrest activity, via inducing robust neuronal differentiation. Rare quiescent Sox2(+) cells survived radiation-enhanced p53(R172P) activation and entered a proliferative state, regenerating tumors. Transcriptomes of Sox2(+) cells resembled quiescent Nestin-expressing progenitors in the developing cerebellum, expressing Olig2 known to suppress p53 and p21 expression. Importantly, high SOX2 expression is associated with poor survival of all four SHH-MB subgroups, independent of TP53 mutational status. CONCLUSIONS: Quiescent Sox2(+) cells are efficiently eliminated by p53-mediated apoptosis, but not cell-cycle arrest and differentiation. Their survival contributes to tumor recurrence due to insufficient p53-pathway activation.
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spelling pubmed-68600042019-11-21 Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence Treisman, Daniel M Li, Yinghua Pierce, Brianna R Li, Chaoyang Chervenak, Andrew P Tomasek, Gerald J Lozano, Guillermina Zheng, Xiaoyan Kool, Marcel Zhu, Yuan Neurooncol Adv Basic and Translational Investigations BACKGROUND: High-intensity therapy effectively treats most TP53 wild-type (TP53-WT) Sonic Hedgehog-subgroup medulloblastomas (SHH-MBs), but often cause long-term deleterious neurotoxicities in children. Recent clinical trials investigating reduction/de-escalation of therapy for TP53-WT SHH-MBs caused poor overall survival. Here, we investigated whether reduced levels of p53-pathway activation by low-intensity therapy potentially contribute to diminished therapeutic efficacy. METHODS: Using mouse SHH-MB models with different p53 activities, we investigated therapeutic efficacy by activating p53-mediated cell-cycle arrest versus p53-mediated apoptosis on radiation-induced recurrence. RESULTS: Upon radiation treatment, p53(WT)-mediated apoptosis was sufficient to eliminate all SHH-MB cells, including Sox2(+) cells. The same treatment eliminated most Sox2(−) bulk tumor cells in SHH-MBs harboring p53(R172P), an apoptosis-defective allele with cell-cycle arrest activity, via inducing robust neuronal differentiation. Rare quiescent Sox2(+) cells survived radiation-enhanced p53(R172P) activation and entered a proliferative state, regenerating tumors. Transcriptomes of Sox2(+) cells resembled quiescent Nestin-expressing progenitors in the developing cerebellum, expressing Olig2 known to suppress p53 and p21 expression. Importantly, high SOX2 expression is associated with poor survival of all four SHH-MB subgroups, independent of TP53 mutational status. CONCLUSIONS: Quiescent Sox2(+) cells are efficiently eliminated by p53-mediated apoptosis, but not cell-cycle arrest and differentiation. Their survival contributes to tumor recurrence due to insufficient p53-pathway activation. Oxford University Press 2019-09-23 /pmc/articles/PMC6860004/ /pubmed/31763624 http://dx.doi.org/10.1093/noajnl/vdz027 Text en © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Basic and Translational Investigations
Treisman, Daniel M
Li, Yinghua
Pierce, Brianna R
Li, Chaoyang
Chervenak, Andrew P
Tomasek, Gerald J
Lozano, Guillermina
Zheng, Xiaoyan
Kool, Marcel
Zhu, Yuan
Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence
title Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence
title_full Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence
title_fullStr Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence
title_full_unstemmed Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence
title_short Sox2(+) cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence
title_sort sox2(+) cells in sonic hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860004/
https://www.ncbi.nlm.nih.gov/pubmed/31763624
http://dx.doi.org/10.1093/noajnl/vdz027
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