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

Robert J. Vanner, Marc Remke, Marco Gallo, Hayden J. Selvadurai, Fiona Coutinho, Lilian Lee, Michelle Kushida, Renee Head, Sorana Morrissy, Xueming Zhu, Tzvi Aviv, Veronique Voisin, Ian D. Clarke, Yisu Li, Andrew J. Mungall, Richard A. Moore, Yussanne Ma, Steven J.M. Jones, Marco A. Marra, David MalkinPaul A. Northcott, Marcel Kool, Stefan M. Pfister, Gary Bader, Konrad Hochedlinger, Andrey Korshunov, Michael D. Taylor, Peter B. Dirks

Research output: Contribution to journalArticlepeer-review

216 Citations (Scopus)

Abstract

Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox2+ cells propagate sonic hedgehog subgroup medulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox2+ cells produce rapidly cycling doublecortin+ progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox2+ cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox2+ cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox2+ cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox2+ cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma.

Original languageEnglish
Pages (from-to)33-47
Number of pages15
JournalCancer Cell
Volume26
Issue number1
DOIs
Publication statusPublished - 14 Jul 2014
Externally publishedYes

Fingerprint

Dive into the research topics of 'Quiescent Sox2+ Cells Drive Hierarchical Growth and Relapse in Sonic Hedgehog Subgroup Medulloblastoma'. Together they form a unique fingerprint.

Cite this