Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries

• Published in: Nature genetics Vol. 49; no. 9; pp. 1408 - 1413
• Main Authors: Boeva, Valentina, Louis-Brennetot, Caroline, Peltier, Agathe, Durand, Simon, Pierre-Eugène, Cécile, Raynal, Virginie, Etchevers, Heather C, Thomas, Sophie, Lermine, Alban, Daudigeos-Dubus, Estelle, Geoerger, Birgit, Orth, Martin F, Grünewald, Thomas G P, Diaz, Elise, Ducos, Bertrand, Surdez, Didier, Carcaboso, Angel M, Medvedeva, Irina, Deller, Thomas, Combaret, Valérie, Lapouble, Eve, Pierron, Gaelle, Grossetête-Lalami, Sandrine, Baulande, Sylvain, Schleiermacher, Gudrun, Barillot, Emmanuel, Rohrer, Hermann, Delattre, Olivier, Janoueix-Lerosey, Isabelle
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2017; Nature Publishing Group
• Subjects: 42/89; 45/15; 631/337/176; 631/67/1678; 631/67/1922; Activator protein 1; Addictions; Agriculture; Animal Genetics and Genomics; Animals; Biochemistry, Molecular Biology; Bioinformatics; Biomedicine; Blotting, Western; Cancer; Cancer cells; Cancer Research; Cell cycle; Cell Line, Tumor - classification; Cell Lineage - drug effects; Cell Lineage - genetics; Chemotherapy; Deoxyribonucleic acid; Development and progression; DNA; Doxycycline - pharmacology; GATA-3 protein; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gene Function; Genetic aspects; Genetic Heterogeneity; Genomes; Genomics; HEK293 Cells; Heterogeneity; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Human Genetics; Humans; letter; Life Sciences; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Modules; Mutation; Neural crest; Neurobiology; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neurons and Cognition; Norepinephrine; Phox2b protein; Physiological aspects; Principal components analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNAi Therapeutics; Single-Cell Analysis; Transcription (Genetics); Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; Xenograft Model Antitumor Assays - methods; France
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3921

Isabelle Janoueix-Lerosey, Valentina Boeva and colleagues analyze the super-enhancer landscape of 25 neuroblastoma cell lines to define core regulatory circuits controlling gene expression programs. They find and functionally characterize two types of cell identity that contribute to the tumor heterogeneity of neuroblastoma.
Neuroblastoma is a tumor of the peripheral sympathetic nervous system
1
, derived from multipotent neural crest cells (NCCs). To define core regulatory circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity, defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 TFs; and a mixed type, further deconvoluted at the single-cell level. Treatment of the mixed type with chemotherapeutic agents resulted in enrichment of NCC-like cells. The noradrenergic module was validated by ChIP-seq. Functional studies demonstrated dependency of neuroblastoma with noradrenergic identity on PHOX2B, evocative of lineage addiction. Most neuroblastoma primary tumors express TFs from the noradrenergic and NCC-like modules. Our data demonstrate a previously unknown aspect of tumor heterogeneity relevant for neuroblastoma treatment strategies.