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

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

Author information

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.

PMID:
24954133
PMCID:
PMC4441014
DOI:
10.1016/j.ccr.2014.05.005
[Indexed for MEDLINE]
Free PMC Article

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