TY  - JOUR
AU  - Treisman, Daniel M
AU  - Li, Yinghua
AU  - Pierce, Brianna R
AU  - Li, Chaoyang
AU  - Chervenak, Andrew P
AU  - Tomasek, Gerald J
AU  - Lozano, Guillermina
AU  - Zheng, Xiaoyan
AU  - Kool, Marcel
AU  - Zhu, Yuan
TI  - Sox2+ cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence.
JO  - Neuro-oncology advances
VL  - 1
IS  - 1
SN  - 2632-2498
CY  - Oxford
PB  - Oxford University Press
M1  - DKFZ-2019-02713
SP  - vdz027
PY  - 2019
N1  -  Neuro-Oncology Advances () = 2632-2498 (import from CrossRef, PubMed, )E-ISSN(s): 2632-2498
AB  - 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.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.Upon radiation treatment, p53WT-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 p53R172P, an apoptosis-defective allele with cell-cycle arrest activity, via inducing robust neuronal differentiation. Rare quiescent Sox2+ cells survived radiation-enhanced p53R172P 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.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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31763624
C2  - pmc:PMC6860004
DO  - DOI:10.1093/noajnl/vdz027
UR  - https://inrepo02.dkfz.de/record/147736
ER  -