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Autor(en) / Beteiligte

Titel

Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries

Ist Teil von

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

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.

Sprache: Englisch
Identifikatoren: ISSN: 1061-4036
eISSN: 1546-1718
DOI: 10.1038/ng.3921
Titel-ID: cdi_hal_primary_oai_HAL_hal_01741718v1

Format: –
Schlagworte: Activator protein 1, Addictions, Animals, Biochemistry, Molecular Biology, Bioinformatics, Blotting, Western, Cancer, Cancer cells, 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, Genetic aspects, Genetic Heterogeneity, Genomes, Genomics, HEK293 Cells, Heterogeneity, Homeodomain Proteins - genetics, Homeodomain Proteins - metabolism, Humans, 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

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