ID #275 Lithium prevents the growth of group 3 medulloblastoma by inducing differentiation.

Abstract

Medulloblastoma (MB) is the most common high-grade pediatric brain tumor, with Group 3 (MB3) representing the most aggressive and therapy resistance subtype. Craniospinal irradiation is central to MB management but while this improves survival, survivors often experience severe, lifelong neurocognitive deficits. Lithium, a clinically approved neuroprotective agent can promote neurogenesis, reduce neuroinflammation, and protect neural stem cells from radiation damage, yet its impact on MB3 tumor biology is not explored.

Here, we created a syngeneic orthotopic mouse model of MB3 and studied the effects of lithium and radiation bothin vitroandin vivo. Lithium significantlyreduced MB3 tumor growth by up to 65%in vivo, with further suppression observed when combined with irradiation, indicating additive antitumor activity. Transcriptomic analyses showed that lithium treatment downregulated oncogenic drivers such as Myc and multiple cellcycle regulators, including Cyclin D1, consistent with a broader suppression of proliferative, stem-like transcriptional programs. Lithium interestingly induced neuronal differentiation signatures characterized by increased expression of NeuroD1, TPPP and Tubb3, together with other markers of neuronal and glial lineage commitment. These changes occurred without induction of apoptosis, supporting a mode of action centered on differentiation and cell state reprogramming rather than overt cytotoxicity.

Together, these findings indicate that lithium can both protect the juvenile brain from radiationinduced injury and directly modulate MB3 tumor cell fates. By promoting neuronal differentiation and reducing tumor growth, lithium emerges as a promising therapeutic adjunct to enhance treatment efficacy while, at the same time, reducing the longterm neurotoxic burden in children with MB3.