... Marsden Hospital, Sutton, UK. 17Department of Cellular Pathology, St George's Hospital NHS Trust, London, ... Henry C. Mandeville16, Leslie R. Bridges17, Andrew J. Martin18, Safa Al-Sarraj19,. Christopher ...... Mackay, A. et al. Integrated ...
Articles https://doi.org/10.1038/s41591-018-0086-7
Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells Mara Vinci1,2,3,23, Anna Burford1,2,3, Valeria Molinari1,2,3, Ketty Kessler1,2,3, Sergey Popov1,2,3,4, Matthew Clarke1,2,3, Kathryn R. Taylor1,2,3,5, Helen N. Pemberton6, Christopher J. Lord6, Alice Gutteridge7, Tim Forshew7, Diana Carvalho 1,2,3, Lynley V. Marshall8, Elizabeth Y. Qin5, Wendy J. Ingram 9,10, Andrew S. Moore 9,10,11, Ho-Keung Ng12, Saoussen Trabelsi13, Dorra H’mida-Ben Brahim13,14, Natacha Entz-Werle15, Stergios Zacharoulis8,24, Sucheta Vaidya8, Henry C. Mandeville16, Leslie R. Bridges17, Andrew J. Martin18, Safa Al-Sarraj19, Christopher Chandler20, Mariona Sunol21, Jaume Mora21, Carmen de Torres21, Ofelia Cruz 21, Angel M. Carcaboso 21, Michelle Monje 22, Alan Mackay1,2,3 and Chris Jones1,2,3* 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
