Sox2
| Autor: | Daniel M. Treisman, Guillermina Lozano, Chaoyang Li, Yinghua Li, Gerald J. Tomasek, Xiaoyan Zheng, Yuan Zhu, Marcel Kool, Brianna R. Pierce, Andrew P. Chervenak |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
p53 Cell cycle checkpoint animal structures granule cell precursor neural precursor Transcriptome OLIG2 03 medical and health sciences 0302 clinical medicine SOX2 medicine Sonic hedgehog Progenitor cell Medulloblastoma biology business.industry Sonic Hedgehog medulloblastoma apoptosis medicine.disease 030104 developmental biology Apoptosis 030220 oncology & carcinogenesis embryonic structures Basic and Translational Investigations Cancer research biology.protein business |
| Zdroj: | Neuro-Oncology Advances |
| ISSN: | 2632-2498 |
| Popis: | 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, 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. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|