Quiescent Sox2+ Cells Drive Hierarchical Growth and Relapse in Sonic Hedgehog Subgroup Medulloblastoma

Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox(2+) cells propagate sonic hedgehog subgroup nnedulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox(2+) cells produce rapidly cycling doublecortin(+) progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox(2+) cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox(2+) cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox(2+) cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox(2+) cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma.