Vanner, Robert J., Remke, Marc, Gallo, Marco, Selvadurai, Hayden J., Coutinho, Fiona, Lee, Lilian, Kushida, Michelle, Head, Renee, Morrissy, Sorana, Zhu, Xueming, Aviv, Tzvi, Voisin, Veronique, Clarke, Ian D., Li, Yisu, Mungall, Andrew J., Moore, Richard A., Ma, Yussanne, Jones, Steven J.M., Marra, Marco A., Malkin, David, Northcott, Paul A., Kool, Marcel, Pfister, Stefan M., Bader, Gary, Hochedlinger, Konrad, Korshunov, Andrey, Taylor, Michael D. and Dirks, Peter B. (2014) Quiescent Sox2+ cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. Cancer cell, 26 (1). pp. 33-47.

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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.

Item Type:	Article
Divisions:	Faculty of Liberal Arts & Sciences
Date Deposited:	18 Oct 2016 17:52
Last Modified:	02 Aug 2021 08:42
URI:	https://openresearch.ocadu.ca/id/eprint/1253

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