Dexamethasone-Induced p57-Mediated Quiescence Drives Chemotherapy Resistance in Sonic Hedgehog Medulloblastoma

Abstract

Medulloblastoma (MB), the most common malignant pediatric brain tumor, remains difficult to cure upon relapse, with only 12.4% of patients surviving five years post-recurrence. While specific quiescent tumor cell populations are known to contribute to treatment-resistance, the molecular mechanisms that maintain quiescence remain poorly defined. Here, we identify the cell cycle inhibitor p57 as a regulator of quiescence and chemotherapy resistance in Sonic Hedgehog (SHH) MB. Nuclear p57 was enriched in Sox2+ and Nestin+ stem-like MB cells compared to proliferative Atoh1+ cells. Inducing p57 expression in SHH MB cells led to a six-fold increase in G0-phase cells and conferred resistance to the frontline chemotherapeutic vincristine. Clinically, dexamethasone is a glucocorticoid given to nearly all MB patients to manage cerebral edema and is administered with wide variability in timing and dosing. We show that dexamethasone significantly increased nuclear p57 levels and expanded the G0 population in both Ptch1+/- and Ptch1+/-;Trp53-/- SHH MB mouse models. Pre-treatment with dexamethasone reduced vincristine sensitivity in SHH MB cells. Together, our findings reveal a clinically relevant and previously unrecognized mechanism of treatment resistance, whereby dexamethasone, despite its benefits in managing edema, may inadvertently contribute to tumor persistence or recurrence by driving a quiescent, drug-resistant state. Addressing the lack of standardization in steroid use or targeting p57 may improve treatment response and reduce recurrence in patients diagnosed with SHH MB.