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

Author:

Saldana-Guerrero Ingrid M.ORCID,Montano-Gutierrez Luis F.ORCID,Boswell KatyORCID,Hafemeister ChristophORCID,Poon EvonORCID,Shaw Lisa E.ORCID,Stavish DylanORCID,Lea Rebecca A.ORCID,Wernig-Zorc Sara,Bozsaky EvaORCID,Fetahu Irfete S.ORCID,Zoescher PeterORCID,Pötschger Ulrike,Bernkopf MarieORCID,Wenninger-Weinzierl Andrea,Sturtzel Caterina,Souilhol Celine,Tarelli Sophia,Shoeb Mohamed R.ORCID,Bozatzi Polyxeni,Rados Magdalena,Guarini MariaORCID,Buri Michelle C.ORCID,Weninger Wolfgang,Putz Eva M.ORCID,Huang MillerORCID,Ladenstein RuthORCID,Andrews Peter W.ORCID,Barbaric IvanaORCID,Cresswell George D.ORCID,Bryant Helen E.ORCID,Distel MartinORCID,Chesler LouisORCID,Taschner-Mandl SabineORCID,Farlik MatthiasORCID,Tsakiridis AnestisORCID,Halbritter FlorianORCID

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

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