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Nat Genet. 2017 Sep;49(9):1408-1413. doi: 10.1038/ng.3921. Epub 2017 Jul 24.

Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries.

Author information

1
Institut Curie, Paris Sciences et Lettres (PSL) Research University, INSERM, U900, Mines-ParisTech, Paris, France.
2
Institut Cochin, Inserm U1016, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, University Paris Descartes UMR-S1016, Paris, France.
3
Institut Curie, PSL Research University, INSERM, U830, Equipe Labellisée Ligue contre le Cancer, Paris, France.
4
Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France.
5
Aix Marseille University, INSERM, Génétique Médicale et Génomique Fonctionnelle (GMGF) UMR S910, Marseille, France.
6
INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
7
Gustave Roussy, Vectorology and Anticancer Therapies, UMR 8203, CNRS, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
8
Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.
9
High Throughput qPCR Facility, Institut de Biologie de l'École Normale Supérieure (IBENS), PSL Research University, Paris, France.
10
LPS-ENS, Université Pierre et Marie Curie (UPMC), Université Denis Diderot, CNRS UMR 8550, PSL, Paris, France.
11
Laser Microdissection Facility, Center for Interdisciplinary Research in Biology (CIRB) Collège de France, Paris, France.
12
Institut de Recerca Sant Joan de Deu, Barcelona, Spain.
13
Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University Frankfurt, Frankfurt am Main, Germany.
14
Centre Léon Bérard, Laboratoire de Recherche Translationnelle, Lyon, France.
15
Institut Curie, Unité de Génétique Somatique, Paris, France.
16
Laboratory Recherche Translationnelle en Oncologie Pédiatrique (RTOP), Laboratoire "Gilles Thomas", Institut Curie, Paris, France.
17
Department of Translational Research, Institut Curie, Paris, France.
18
SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France.

Abstract

Neuroblastoma is a tumor of the peripheral sympathetic nervous system, 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.

PMID:
28740262
DOI:
10.1038/ng.3921
[Indexed for MEDLINE]

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