Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries

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

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.

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor / classification
  • Cell Lineage / drug effects
  • Cell Lineage / genetics*
  • Doxycycline / pharmacology
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genetic Heterogeneity
  • HEK293 Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Neuroblastoma / drug therapy
  • Neuroblastoma / genetics*
  • Neuroblastoma / metabolism
  • RNA Interference
  • RNAi Therapeutics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Single-Cell Analysis
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Xenograft Model Antitumor Assays / methods

Substances

  • Homeodomain Proteins
  • NBPhox protein
  • Transcription Factors
  • Doxycycline