Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma.

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.
Authors	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 Malkin, Paul A Northcott, Marcel Kool, Stefan M Pfister, Gary Bader, Konrad Hochedlinger, Andrey Korshunov, Michael D Taylor, Peter B Dirks
Journal	Cancer cell (Cancer Cell) Vol. 26 Issue 1 Pg. 33-47 (Jul 14 2014) ISSN: 1878-3686 [Electronic] United States
PMID	24954133 (Publication Type: Journal Article)
Copyright	Copyright © 2014 Elsevier Inc. All rights reserved.
Chemical References	Antigens, Nuclear Antineoplastic Agents Biomarkers, Tumor DNA-Binding Proteins Doublecortin Domain Proteins Hedgehog Proteins Microtubule-Associated Proteins Nerve Tissue Proteins NeuN protein, mouse Neuropeptides Nuclear Proteins Patched Receptors Receptors, Cell Surface Receptors, G-Protein-Coupled SHH protein, human SMO protein, human SOX2 protein, human SOXB1 Transcription Factors Shh protein, mouse Smo protein, mouse Smoothened Receptor Sox2 protein, mouse neuronal nuclear antigen NeuN, human Plicamycin
Topics	Animals Antigens, Nuclear (metabolism) Antineoplastic Agents (pharmacology) Biomarkers, Tumor (genetics, metabolism) Cell Lineage Cell Proliferation (drug effects) Cerebellar Neoplasms (drug therapy, genetics, metabolism, pathology) DNA-Binding Proteins Dose-Response Relationship, Drug Doublecortin Domain Proteins Drug Resistance, Neoplasm Gene Expression Profiling Gene Expression Regulation, Neoplastic Hedgehog Proteins (genetics, metabolism) Medulloblastoma (drug therapy, genetics, metabolism) Mice Mice, Transgenic Microtubule-Associated Proteins (metabolism) Molecular Sequence Data Neoplasm Recurrence, Local Nerve Tissue Proteins (metabolism) Neurogenesis Neuropeptides (metabolism) Nuclear Proteins (metabolism) Patched Receptors Plicamycin (pharmacology) Prognosis Receptors, Cell Surface (genetics, metabolism) Receptors, G-Protein-Coupled (metabolism) SOXB1 Transcription Factors (genetics, metabolism) Smoothened Receptor Time Factors Tumor Cells, Cultured

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