Journal Article

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq

Neftel, Cyril, Dorfer, Christian, Pelton, Kristine, Czech, Thomas, Mathewson, Nathan D., Egervari, Kristof, Frosch, Matthew P., Wucherpfennig, Kai W., Beck, Alexander, Shaw, McKenzie L., Nguyen, Quang-De, Goumnerova, Liliana, Escalante, Leah E., Yizhak, Keren, Popović, Mara, Gojo, Johannes, Regev, Aviv, Filbin, Mariella G., Beroukhim, Rameen, Bandopadhayay, Pratiti, Martinez-Lage, Maria, Monje, Michelle, Fritsch, Gerhard, Hebert, Christine M., Slavc, Irene, Carcaboso, Angel M., Golub, Todd R., Sinai, Claire, Azizi, Amedeo, Mora, Jaume, Suvà, Mario L., Luo, Christina C., Lavarino, Cinzia, Kieran, Mark W., Batchelor, Tracy T., Frank, Nelli, van Galen, Peter, Mount, Christopher, Ligon, Keith L., Louis, David N., Rozenblatt-Rosen, Orit, Mylvaganam, Ravindra, Bonal, Dennis M., Bernstein, Bradley E., Hovestadt, Volker, Haberler, Christine, Tirosh, Itay, Getz, Gad, Peyrl, Andreas

2018

Overview

Diffuse midline gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) are an aggressive type of childhood cancer with few options for treatment. Filbin et al. used a single-cell sequencing approach to study the oncogenic programs, genetics, and cellular hierarchies of H3K27M-glioma. Tumors were mainly composed of cells resembling oligodendrocyte precursor cells, whereas differentiated malignant cells were a smaller fraction. In comparison with other gliomas, these cancers had distinct oncogenic programs and stem cell–like profiles that contributed to their stable tumor-propagating potential. The analysis also identified a lineage-specific marker that may be useful in developing therapies. Science , this issue p. 331 Single-cell analyses of H3K27M glioma defines a putative developmental hierarchy that differs from other gliomas. 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.

• Publisher: The American Association for the Advancement of Science
• Subject: Anatomy / Brain Neoplasms - genetics / Brain Neoplasms - pathology / Brain tumors / Carcinogenesis - genetics / Cell Proliferation / Central nervous system / Children / Developmental Programs / Gene sequencing / Genetics / Glial stem cells / Glioma / Glioma - genetics / Glioma - pathology / Glioma cells / Hierarchies / Histone H3 / Histones - metabolism / Humans / Methionine / Mitogen-Activated Protein Kinase 7 - genetics / Model matching / Mutation / Oligodendroglia - metabolism / Oligodendroglia - pathology / Oncogenes / Precursors / Receptor, Platelet-Derived Growth Factor alpha - genetics / Receptor, Platelet-Derived Growth Factor alpha - metabolism / Ribonucleic acid / RNA / Sequence Analysis, RNA - methods / Signaling / Single-Cell Analysis - methods / Stem cells / Therapeutic applications / Tumorigenesis / Tumors