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Nat Med. 2018 Aug;24(8):1204-1215. doi: 10.1038/s41591-018-0086-7. Epub 2018 Jul 2.

Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells.

Author information

1
Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
2
Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
3
Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
4
Bambino Gesù Children's Hospital-IRCCS, Rome, Italy.
5
Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK.
6
Stanford University School of Medicine, Stanford, CA, USA.
7
CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
8
UCL Cancer Institute, University College London, London, UK.
9
Paediatric Oncology Drug Development Team, Children and Young People's Unit, Royal Marsden Hospital, Sutton, UK.
10
UQ Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
11
Oncology Services Group, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland, Australia.
12
The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
13
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
14
Department of Cytogenetics and Reproductive Biology, Farhat HACHED Hospital, Sousse, Tunisia.
15
Faculty of Medicine, Sousse, Tunisia.
16
Centre Hospitalier Régional et Universitaire Hautepierre, Strasbourg, France.
17
Department of Pediatric Hematology Oncology, Columbia University Medical Center, New York, NY, USA.
18
Department of Radiotherapy, Royal Marsden Hospital, Sutton, UK.
19
Department of Cellular Pathology, St George's Hospital NHS Trust, London, UK.
20
Department of Neurosurgery, St George's Hospital NHS Trust, London, UK.
21
Department of Neuropathology, Kings College Hospital, London, UK.
22
Department of Neurosurgery, Kings College Hospital, London, UK.
23
Hospital Sant Joan de Deu, Barcelona, Spain.
24
Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
25
Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK. chris.jones@icr.ac.uk.
26
Division of Molecular Pathology, The Institute of Cancer Research, London, UK. chris.jones@icr.ac.uk.
27
Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK. chris.jones@icr.ac.uk.

Abstract

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.

PMID:
29967352
PMCID:
PMC6086334
[Available on 2019-01-02]
DOI:
10.1038/s41591-018-0086-7

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