Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma

Claire Vinel, Gabriel Rosser, Loredana Guglielmi, Myrianni Constantinou, Nicola Pomella, Xinyu Zhang, James R. Boot, Tania A. Jones, Thomas O. Millner, Anaelle A. Dumas, Vardhman Rakyan, Jeremy Rees, Jamie L. Thompson, Juho Vuononvirta, Suchita Nadkarni, Tedani El Assan, Natasha Aley, Yung-Yao Lin, Pentao Liu, Sven Nelander, Denise Sheer, Catherine L. R. Merry, Federica Marelli-Berg, Sebastian Brandner and Silvia Marino ()
Additional contact information
Claire Vinel: Queen Mary University London
Gabriel Rosser: Queen Mary University London
Loredana Guglielmi: Queen Mary University London
Myrianni Constantinou: Queen Mary University London
Nicola Pomella: Queen Mary University London
Xinyu Zhang: Queen Mary University London
James R. Boot: Queen Mary University London
Tania A. Jones: Queen Mary University London
Thomas O. Millner: Queen Mary University London
Anaelle A. Dumas: Queen Mary University London
Vardhman Rakyan: Queen Mary University London
Jeremy Rees: University College London Hospitals NHS Foundation Trust
Jamie L. Thompson: University of Nottingham
Juho Vuononvirta: Queen Mary University London
Suchita Nadkarni: Queen Mary University London
Tedani El Assan: University College London Hospitals NHS Foundation Trust
Natasha Aley: UCL Queen Square Institute of Neurology
Yung-Yao Lin: Queen Mary University London
Pentao Liu: The University of Hong Kong
Sven Nelander: Uppsala University
Denise Sheer: Queen Mary University London
Catherine L. R. Merry: University of Nottingham
Federica Marelli-Berg: Queen Mary University London
Sebastian Brandner: University College London Hospitals NHS Foundation Trust
Silvia Marino: Queen Mary University London

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Epigenetic mechanisms which play an essential role in normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC) are also responsible for some of the changes in the glioblastoma (GBM) genome. Here we develop a strategy to compare the epigenetic and transcriptional make-up of primary GBM cells (GIC) with patient-matched expanded potential stem cell (EPSC)-derived NSC (iNSC). Using a comparative analysis of the transcriptome of syngeneic GIC/iNSC pairs, we identify a glycosaminoglycan (GAG)-mediated mechanism of recruitment of regulatory T cells (Tregs) in GBM. Integrated analysis of the transcriptome and DNA methylome of GBM cells identifies druggable target genes and patient-specific prediction of drug response in primary GIC cultures, which is validated in 3D and in vivo models. Taken together, we provide a proof of principle that this experimental pipeline has the potential to identify patient-specific disease mechanisms and druggable targets in GBM.

Date: 2021
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DOI: 10.1038/s41467-021-26297-6

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