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 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.