A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

Abstract

Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNAs impair the specification of trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. This effect is exacerbated upon overexpression of MYCN, whose amplification co-occurs with CNAs in NB. Moreover, CNAs potentiate the pro-tumourigenic effects of MYCN and mutant NC cells resemble NB cells in tumours. These changes correlate with a stepwise aberration of developmental transcription factor networks. Together, our results sketch a mechanistic framework for the CNA-driven initiation of embryonal tumours.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

* The entire manuscript has been substantially revised. In particular, we added data based on cellular assays (apoptosis, DNA damage), scRNA-seq (10x Genomics and Parse Bio), WES (SNV and CNA analyses), integration with public genomics data (SEQC and others), and mouse xenografts using the previously used stem cell lines and new derivatives (inducing MYCN in WT and 17q-only background). All figures have been updated and we added a new figure (Fig. 5) and several supplementary figures.