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 Boot, T. Alwyn Jones, Thomas O Millner, Anaëlle Dumas, Vardhman K. Rakyan, Jeremy Rees, Jamie Thompson, Juho Vuononvirta, Suchita Nadkarni, Tedani El Assan, Natasha Aley, Yung‐Yao Lin, Pentao Liu, Sven Nelander, Denise Sheer, Catherine L.R. Merry, Federica M. Marelli‐Berg, Sebastian Brandner, Silvia Marino
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.