Journal Article

DKFZ-2019-02713

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Sox2+ cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence.

Treisman, D. M. ; Li, Y. ; Pierce, B. R. ; Li, C. ; Chervenak, A. P. ; Tomasek, G. J. ; Lozano, G. ; Zheng, X. ; Kool, M.DKFZ* ; Zhu, Y.

2019
Oxford University Press Oxford

This record in other databases:  

Please use a persistent id in citations: doi:10.1093/noajnl/vdz027

Abstract: 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.

Note: Neuro-Oncology Advances () = 2632-2498 (import from CrossRef, PubMed, )E-ISSN(s): 2632-2498

---

Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK Heidelberg (L101)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2019

---

Database coverage:
; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Emerging Sources Citation Index ; Fees ; Web of Science Core Collection

---