Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries

V Boeva, C Louis-Brennetot, A Peltier, S Durand… - Nature …, 2017 - nature.com
V Boeva, C Louis-Brennetot, A Peltier, S Durand, C Pierre-Eugène, V Raynal, HC Etchevers
Nature genetics, 2017nature.com
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 …
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.
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