title: 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: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Robert J
authors: RJ
authors: Vanner
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Marc
authors: M
authors: Remke
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
authors: Marco
authors: M
authors: Gallo
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
authors: Hayden J
authors: HJ
authors: Selvadurai
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Fiona
authors: F
authors: Coutinho
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
authors: Lilian
authors: L
authors: Lee
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
authors: Michelle
authors: M
authors: Kushida
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
authors: Renee
authors: R
authors: Head
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
authors: Sorana
authors: S
authors: Morrissy
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
authors: Xueming
authors: X
authors: Zhu
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
authors: Tzvi
authors: T
authors: Aviv
authors: The Donnelly Centre, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Veronique
authors: V
authors: Voisin
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada; OCAD University, Toronto, ON M5T1W1, Canada.
authors: Ian D
authors: ID
authors: Clarke
authors: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
authors: Yisu
authors: Y
authors: Li
authors: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
authors: Andrew J
authors: AJ
authors: Mungall
authors: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
authors: Richard A
authors: RA
authors: Moore
authors: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
authors: Yussanne
authors: Y
authors: Ma
authors: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
authors: Steven J M
authors: SJ
authors: Jones
authors: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
authors: Marco A
authors: MA
authors: Marra
authors: Division of Hematology/Oncology, HSC, Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: David
authors: D
authors: Malkin
authors: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany.
authors: Paul A
authors: PA
authors: Northcott
authors: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany.
authors: Marcel
authors: M
authors: Kool
authors: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany; Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
authors: Stefan M
authors: SM
authors: Pfister
authors: The Donnelly Centre, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Gary
authors: G
authors: Bader
authors: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors: Konrad
authors: K
authors: Hochedlinger
authors: Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Centre, DKFZ, 69120 Heidelberg, Germany.
authors: Andrey
authors: A
authors: Korshunov
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Michael D
authors: MD
authors: Taylor
authors: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: peter.dirks@sickkids.ca.
authors: Peter B
authors: PB
authors: Dirks
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000089622:Doublecortin Domain Proteins; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009364:Neoplasm Recurrence, Local; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000072079:Patched Receptors; D008926:Plicamycin / Q000494:pharmacology; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000072086:Smoothened Receptor; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000089622:Doublecortin Domain Proteins; D053823:Hedgehog Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009479:Neuropeptides; D009687:Nuclear Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C527783:Sox2 protein, mouse; C506808:neuronal nuclear antigen NeuN, human; D008926:Plicamycin