期刊
NATURE GENETICS
卷 49, 期 9, 页码 1408-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3921
关键词
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资金
- Institut Curie
- INSERM
- Ligue Nationale contre le Cancer (Equipe Labellisee)
- Societe Francaise de Lutte contre les Cancers et les Leucemies de l'Enfant et l'Adolescent
- Institut National du Cancer [PRT-K14-061, PHRC IC 2007-2009, PHRC-K14-175),]
- Association Hubert Gouin Enfance and Cancer
- Les Bagouz a Manon, les amis de Claire
- Courir pour Mathieu
- Dans les pas du Geant
- Olivier Chape
- Fondation ARC [MAPY201501241]
- Societe Francaise de Lutte contre les Cancers et les Leucemies de l'Enfant et l'Adolescent (Fondation Enfants et Sante)
- Fondation AREMIG
- Association Thibault BRIET
- Agence Nationale de la Recherche (Investissements d'Avenir program) [ANR-10-EQPX-03, ANR-10-INBS-09-08]
- Canceropole Ile-de-France
- SiRIC-Curie program - SiRIC Grant [INCa-DGOS-4654]
- Region Ile-de-France [21016711]
- Annenberg Foundation [11-385]
- ATIP-Avenir Program
- ARC Foundation [ARC-RAC16002KSA-R15093KS]
- Worldwide Cancer Research [WCR16-1294 R16100KK]
- Who Am I? Laboratory of Excellence [ANR-11-LABX-0071]
- French Government through its Investissement d' Avenir program [ANR-11-IDEX-000502]
- Mayent-Rothschild program from Institut Curie
- Wilhelm-Sander-Stiftung
- LMU Munich's Institutional Strategy LMUexcellent
- Mehr LEBEN fur krebskranke Kinder-Bettina-Brau-Stiftung
- Walter Schulz Foundation
- Wilhelm-Sander-Stiftung [2016.167.1]
- German Cancer Aid [DKH-111886, DKH-70112257]
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.
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