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 Malkin; Paul A Northcott; Marcel Kool; Stefan M Pfister; Gary Bader; Konrad Hochedlinger; Andrey Korshunov; Michael D Taylor; Peter B Dirks

doi:10.1016/j.ccr.2014.05.005

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

Cancer Cell. 2014 Jul 14;26(1):33-47. doi: 10.1016/j.ccr.2014.05.005. Epub 2014 Jun 19.

Authors

Robert J Vanner¹, Marc Remke², Marco Gallo³, Hayden J Selvadurai³, Fiona Coutinho¹, Lilian Lee³, Michelle Kushida³, Renee Head³, Sorana Morrissy³, Xueming Zhu³, Tzvi Aviv³, Veronique Voisin⁴, Ian D Clarke⁵, Yisu Li⁶, Andrew J Mungall⁶, Richard A Moore⁶, Yussanne Ma⁶, Steven J M Jones⁶, Marco A Marra⁶, David Malkin⁷, Paul A Northcott⁸, Marcel Kool⁸, Stefan M Pfister⁹, Gary Bader⁴, Konrad Hochedlinger¹⁰, Andrey Korshunov¹¹, Michael D Taylor², Peter B Dirks¹²

Affiliations

¹ 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.
² 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.
³ 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.
⁴ The Donnelly Centre, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁵ 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.
⁶ Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
⁷ Division of Hematology/Oncology, HSC, Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁸ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany.
⁹ 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.
¹⁰ Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
¹¹ Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Centre, DKFZ, 69120 Heidelberg, Germany.
¹² 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.

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.

MeSH terms

Animals
Antigens, Nuclear / metabolism
Antineoplastic Agents / pharmacology
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Cell Lineage
Cell Proliferation* / drug effects
Cerebellar Neoplasms / drug therapy
Cerebellar Neoplasms / genetics
Cerebellar Neoplasms / metabolism*
Cerebellar Neoplasms / pathology
DNA-Binding Proteins
Dose-Response Relationship, Drug
Doublecortin Domain Proteins
Drug Resistance, Neoplasm
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism*
Medulloblastoma / drug therapy
Medulloblastoma / genetics
Medulloblastoma / 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
Receptors, Cell Surface / metabolism
Receptors, G-Protein-Coupled / metabolism
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism*
Smoothened Receptor
Time Factors
Tumor Cells, Cultured

Substances

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

Associated data

GENBANK/GSE48766
GENBANK/GSE50765

Abstract

MeSH terms

Substances

Associated data

Grants and funding