Abstract
AbstractEarly 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.
Funder
Alex’s Lemonade Stand Foundation for Childhood Cancer
Austrian Science Fund
RCUK | Biotechnology and Biological Sciences Research Council
Cancer Research UK
Österreichischen Akademie der Wissenschaften
U.S. Department of Health & Human Services | National Institutes of Health
RCUK | Medical Research Council
Children’s Cancer and Leukaemia Group
Vienna Science and Technology Fund
EC | Horizon 2020 Framework Programme
Publisher
Springer Science and Business Media LLC
Cited by
2 articles.
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