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 wild-type (-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 -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-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 , an apoptosis-defective allele with cell-cycle arrest activity, via inducing robust neuronal differentiation. Rare quiescent Sox2 cells survived radiation-enhanced p53 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 expression is associated with poor survival of all four SHH-MB subgroups, independent of 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.