Abstract
Superenhancer-associated transcriptional networks promote neuroblastoma heterogeneity.
Major finding: Superenhancer-associated transcriptional networks promote neuroblastoma heterogeneity.
Approach: CD133+ and CD133− isogenic neuroblastoma cell lines were generated and molecularly characterized.
Impact: Targeting mesenchymal CD133+ neuroblastoma cells may impede relapse.
Neuroblastoma is a pediatric cancer that arises from sympathetic nervous tissue, most frequently in the adrenal glands, and exhibits significant intratumor heterogeneity; however, mechanisms underlying neuroblastoma heterogeneity have not been elucidated because neuroblastoma harbors few somatic mutations. Evidence suggests that superenhancers are master regulators of lineage identity; to elucidate the role of superenhancers in neuroblastoma intratumor heterogeneity, van Groningen and colleagues demonstrated that neuroblastoma is made up of tumor cells with two highly divergent phenotypes, recapitulating lineage developmental stages. Molecular and phenotypic characterization of several isogenic pairs of CD133+ and CD133− cell lines derived from the same patients revealed that isogenic pairs harbored similar genomic alterations; however, CD133+ cell lines exhibited a motile phenotype and expressed a mesenchymal-associated gene signature, while CD133− cell lines exhibited a nonmigratory phenotype and expressed an adrenergic differentiation–associated gene signature, thus resembling classic neuroblastoma of adrenergic lineage. Further, expression profiling of established neuroblastoma cell lines revealed that the mesenchymal-associated gene signature scores of mesenchymal-type cell lines resembled those of human neural crest–derived cell lines, suggesting that mesenchymal-type neuroblastoma cells resemble precursors of the adrenergic lineage. Mesenchymal and adrenergic neuroblastoma cell lines were shown to exhibit divergent mesenchymal- and adrenergic-specific superenhancer patterns and were significantly associated with, respectively, mesenchymal-specific and adrenergic-specific transcription factor genes. Expression of the mesenchymal superenhancer-associated transcription factor PRRX1 induced the reprogramming of adrenergic neuroblastoma cell lines to a mesenchymal phenotype and the expression of mesenchymal markers. The mesenchymal cell type was in vitro more resistant to chemotherapeutic drugs than the adrenergic cell type. A clinical implication was suggested by the finding that mesenchymal cells were enriched in post-treatment and relapsed neuroblastomas as compared to, respectively, pretreatment and primary neuroblastomas. These results identify the superenhancer-mediated regulatory programs that drive neuroblastoma plasticity and identify a cell type that is chemoresistant and may play a role in relapse development.
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