Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.
Mariella G FilbinMichael MintsVolker HovestadtMcKenzie L ShawLeah E EscalanteNathan D MathewsonCyril NeftelNelli FrankKristine PeltonChristine M HebertChristine HaberlerKeren YizhakJohannes GojoKristof EgervariChristopher MountPeter van GalenDennis M BonalQuang-De NguyenAlexander BeckClaire SinaiThomas CzechChristian DorferLiliana GoumnerovaCinzia LavarinoAngel Montero CarcabosoJaume MoraRavindra MylvaganamChristina C LuoAndreas PeyrlMara PopovićAmedeo A AziziTracy T BatchelorMatthew P FroschMaria Martinez-LageMark W KieranPratiti BandopadhayayRameen BeroukhimGerhard FritschGad A GetzOrit Rozenblatt-RosenKai W WucherpfennigDavid N LouisMichelle MonjeIrene SlavcKeith L LigonTodd R GolubAviv RegevBradley E BernsteinMario L SuvàPublished in: Science (New York, N.Y.) (2018)
Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.