title: Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner.
abstract: Epigenetic changes are frequently observed in cancer. However, their role in establishing or sustaining the malignant state has been difficult to determine due to the lack of experimental tools that enable resetting of epigenetic abnormalities. To address this, we applied induced pluripotent stem cell (iPSC) reprogramming techniques to invoke widespread epigenetic resetting of glioblastoma (GBM)-derived neural stem (GNS) cells. GBM iPSCs (GiPSCs) were subsequently redifferentiated to the neural lineage to assess the impact of cancer-specific epigenetic abnormalities on tumorigenicity. GiPSCs and their differentiating derivatives display widespread resetting of common GBM-associated changes, such as DNA hypermethylation of promoter regions of the cell motility regulator TES (testis-derived transcript), the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C; p57KIP2), and many polycomb-repressive complex 2 (PRC2) target genes (e.g., SFRP2). Surprisingly, despite such global epigenetic reconfiguration, GiPSC-derived neural progenitors remained highly malignant upon xenotransplantation. Only when GiPSCs were directed to nonneural cell types did we observe sustained expression of reactivated tumor suppressors and reduced infiltrative behavior. These data suggest that imposing an epigenome associated with an alternative developmental lineage can suppress malignant behavior. However, in the context of the neural lineage, widespread resetting of GBM-associated epigenetic abnormalities is not sufficient to override the cancer genome.
authors.affiliation: Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Stricker
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.forename: Pär G
authors.initials: PG
authors.lastname: Engström
authors.forename: Helena
authors.initials: H
authors.lastname: Carén
authors.forename: Kathreena M
authors.initials: KM
authors.lastname: Kurian
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takashima
authors.forename: Colin
authors.initials: C
authors.lastname: Watts
authors.forename: Michael
authors.initials: M
authors.lastname: Way
authors.forename: Peter
authors.initials: P
authors.lastname: Dirks
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pollard
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D058953:Neural Stem Cells / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology; D014183:Transplantation, Heterologous