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

Mara Vinci, Anna Burford, Valeria Molinari, Ketty Kessler, Sergey Popov, Matthew Clarke, Kathryn R Taylor, Helen N Pemberton, Christopher J Lord, Alice Gutteridge, Tim Forshew, Diana Carvalho, Lynley V Marshall, Elizabeth Y Qin, Wendy J Ingram, Andrew S Moore, Ho-Keung Ng, Saoussen Trabelsi, Dorra H'mida-Ben Brahim, Natacha Entz-WerleStergios Zacharoulis, Sucheta Vaidya, Henry C Mandeville, Leslie R Bridges, Andrew J Martin, Safa Al-Sarraj, Christopher Chandler, Mariona Sunol, Jaume Mora, Carmen de Torres, Ofelia Cruz, Angel M Carcaboso, Michelle Monje, Alan Mackay, Chris Jones

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1204-1215
Number of pages12
JournalNature Medicine
Volume24
Issue number8
DOIs
Publication statusPublished - Aug 2018
Externally publishedYes

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