Oligodendroglioma intra-tumor heterogeneity
Itay Tirosh, Andrew S. Venteicher, Christine Hebert, Leah E. Escalante, Anoop P. Patel, Keren Yizhak, Jonathan M. Fisher, Christopher Rodman, Christopher Mount, Mariella G. Filbin, Cyril Neftel, Niyati Desai, Jackson Nyman, Benjamin Izar, Christina C. Luo, Joshua M. Francis, Aanand A. Patel, Maristela L. Onozato, Nicolo Riggi, Kenneth J. Livak, Dave Gennert, Rahul Satija, Brian V. Nahed, William T. Curry, Robert L. Martuza, Ravindra Mylvaganam, A. John Iafrate, Matthew P. Frosch, Todd R. Golub, Miguel N. Rivera, Gad Getz, Orit Rozenblatt-Rosen, Daniel P. Cahill, Michelle Monje, Bradley E. Bernstein, David N. Louis, Aviv Regev, Mario L. Suvà. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma Nature 539, 309–313 doi:10.1038/nature20123
Contact person: Itay Tirosh, tirosh.itay@gmail.com
Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny1. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.
a, CNV profiles inferred from scRNA-seq (top) and DNA whole-exome sequencing (WES) (bottom) of oligodendrogliomas. Cells (rows, n = 4,347) are ordered from non-tumoural cells (NT, n = 303) to cancer cells (n = 4,044), ordered into six oligodendrogliomas. b, In MGH36 and MGH97, cells are ordered by CNVs, with zoomed in view shown. c, PCA of malignant cells. Shown are PC1 (x axis) versus PC2 and PC3 (y axis) scores of cells from three tumours based on a single combined PCA. d, Astrocyte-like and oligodendrocyte-like signatures. Relative expression of genes correlated most positively (bottom) or negatively (top) with PC1, in cancer cells from each of the three tumours (marked as in c), ranked by PC1 scores. Selected astrocyte (AC) and oligodendrocyte (OC) marker genes are highlighted. e, Relative expression of the mice orthologues of the genes shown in d (log2-ratio of the respective cell type compared to the average of oligodendrocyte, astrocyte, OPC and neurons).
