Open Access
Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma
Itay Tirosh,Andrew S. Venteicher,Andrew S. Venteicher,Christine Hebert,Christine Hebert,Leah E. Escalante,Leah E. Escalante,Anoop P. Patel,Keren Yizhak,Keren Yizhak,Jonathan M. Fisher,Christopher Rodman,Christopher Mount,Mariella G. Filbin,Mariella G. Filbin,Cyril Neftel,Cyril Neftel,Niyati Desai,Jackson Nyman,Benjamin Izar,Christina C. Luo,Joshua M. Francis,Joshua M. Francis,Aanand A. Patel,Maristela L. Onozato,Nicolo Riggi,Kenneth J. Livak,David Gennert,Rahul Satija,Brian V. Nahed,William T. Curry,Robert L. Martuza,Ravindra Mylvaganam,A. John Iafrate,Matthew P. Frosch,Todd R. Golub,Todd R. Golub,Todd R. Golub,Miguel Rivera,Miguel Rivera,Gad Getz,Gad Getz,Orit Rozenblatt-Rosen,Daniel P. Cahill,Michelle Monje,Bradley E. Bernstein,Bradley E. Bernstein,David N. Louis,Aviv Regev,Aviv Regev,Mario L. Suvà,Mario L. Suvà +51 more
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TLDR
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.Abstract:
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 progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant 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.read more
Citations
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SCENIC: single-cell regulatory network inference and clustering.
Sara Aibar,Carmen Bravo González-Blas,Thomas Moerman,Vân Anh Huynh-Thu,Hana Imrichova,Gert Hulselmans,Florian Rambow,Jean-Christophe Marine,Pierre Geurts,Jan Aerts,Joost van den Oord,Zeynep Kalender Atak,Jasper Wouters,Stein Aerts +13 more
TL;DR: On a compendium of single-cell data from tumors and brain, it is demonstrated that cis-regulatory analysis can be exploited to guide the identification of transcription factors and cell states.
Journal ArticleDOI
Reversed graph embedding resolves complex single-cell trajectories.
TL;DR: Monocle 2, an algorithm that uses reversed graph embedding to describe multiple fate decisions in a fully unsupervised manner, is applied to two studies of blood development and found that mutations in the genes encoding key lineage transcription factors divert cells to alternative fates.
Journal ArticleDOI
Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer
Sidharth V. Puram,Itay Tirosh,Itay Tirosh,Anuraag S. Parikh,Anoop P. Patel,Keren Yizhak,Shawn M. Gillespie,Shawn M. Gillespie,Christopher Rodman,Christina L. Luo,Edmund A. Mroz,Kevin S. Emerick,Daniel G. Deschler,Daniel G. Deschler,Mark A. Varvares,Mark A. Varvares,Ravi Mylvaganam,Orit Rozenblatt-Rosen,James W. Rocco,James W. Rocco,James W. Rocco,William C. Faquin,Derrick T. Lin,Derrick T. Lin,Aviv Regev,Aviv Regev,Aviv Regev,Bradley E. Bernstein,Bradley E. Bernstein +28 more
TL;DR: In this article, the authors profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases.
Journal ArticleDOI
The Human Cell Atlas
Aviv Regev,Aviv Regev,Aviv Regev,Sarah A. Teichmann,Sarah A. Teichmann,Sarah A. Teichmann,Eric S. Lander,Eric S. Lander,Eric S. Lander,Ido Amit,Christophe Benoist,Ewan Birney,Bernd Bodenmiller,Bernd Bodenmiller,Peter J. Campbell,Peter J. Campbell,Piero Carninci,Menna R. Clatworthy,Hans Clevers,Bart Deplancke,Ian Dunham,James Eberwine,Roland Eils,Roland Eils,Wolfgang Enard,Andrew Farmer,Lars Fugger,Berthold Göttgens,Nir Hacohen,Nir Hacohen,Muzlifah Haniffa,Martin Hemberg,Seung K. Kim,Paul Klenerman,Paul Klenerman,Arnold R. Kriegstein,Ed S. Lein,Sten Linnarsson,Emma Lundberg,Emma Lundberg,Joakim Lundeberg,Partha P. Majumder,John C. Marioni,John C. Marioni,John C. Marioni,Miriam Merad,Musa M. Mhlanga,Martijn C. Nawijn,Mihai G. Netea,Garry P. Nolan,Dana Pe'er,Anthony Phillipakis,Chris P. Ponting,Stephen R. Quake,Wolf Reik,Wolf Reik,Wolf Reik,Orit Rozenblatt-Rosen,Joshua R. Sanes,Rahul Satija,Ton N. Schumacher,Alex K. Shalek,Alex K. Shalek,Alex K. Shalek,Ehud Shapiro,Padmanee Sharma,Jay W. Shin,Oliver Stegle,Michael R. Stratton,Michael J. T. Stubbington,Fabian J. Theis,Matthias Uhlen,Matthias Uhlen,Alexander van Oudenaarden,Allon Wagner,Fiona M. Watt,Jonathan S. Weissman,Barbara J. Wold,Ramnik J. Xavier,Nir Yosef,Nir Yosef,Human Cell Atlas Meeting Participants +81 more
TL;DR: An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease.
Journal ArticleDOI
An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma
Cyril Neftel,Julie Laffy,Mariella G. Filbin,Toshiro Hara,Marni E. Shore,Marni E. Shore,Gilbert J. Rahme,Gilbert J. Rahme,Alyssa R. Richman,Alyssa R. Richman,Dana Silverbush,Dana Silverbush,McKenzie Shaw,Christine M. Hebert,Christine M. Hebert,John M. DeWitt,John M. DeWitt,Simon Gritsch,Simon Gritsch,Elizabeth M. Perez,Elizabeth M. Perez,L. Nicolas Gonzalez Castro,Xiaoyang Lan,Xiaoyang Lan,Nicholas Druck,Christopher Rodman,Danielle Dionne,Alexander Kaplan,Mia Bertalan,Julia L. Small,Kristine Pelton,Sarah Becker,Dennis M. Bonal,Quang-Dé Nguyen,Rachel L. Servis,Jeremy M. Fung,Ravindra Mylvaganam,Lisa Mayr,Johannes Gojo,Christine Haberler,René Geyeregger,Thomas Czech,Irene Slavc,Brian V. Nahed,William T. Curry,Bob S. Carter,Hiroaki Wakimoto,Priscilla K. Brastianos,Tracy T. Batchelor,Anat Stemmer-Rachamimov,Maria Martinez-Lage,Matthew P. Frosch,Ivan Stamenkovic,Nicolo Riggi,Esther Rheinbay,Esther Rheinbay,Michelle Monje,Orit Rozenblatt-Rosen,Daniel P. Cahill,Anoop P. Patel,Tony Hunter,Inder M. Verma,Keith L. Ligon,Keith L. Ligon,David N. Louis,Aviv Regev,Aviv Regev,Bradley E. Bernstein,Bradley E. Bernstein,Itay Tirosh,Mario L. Suvà,Mario L. Suvà +71 more
TL;DR: It is found that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity.
References
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