학술논문
A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations
Document Type
article
Author
Ingrid M. Saldana-Guerrero; Luis F. Montano-Gutierrez; Katy Boswell; Christoph Hafemeister; Evon Poon; Lisa E. Shaw; Dylan Stavish; Rebecca A. Lea; Sara Wernig-Zorc; Eva Bozsaky; Irfete S. Fetahu; Peter Zoescher; Ulrike Pötschger; Marie Bernkopf; Andrea Wenninger-Weinzierl; Caterina Sturtzel; Celine Souilhol; Sophia Tarelli; Mohamed R. Shoeb; Polyxeni Bozatzi; Magdalena Rados; Maria Guarini; Michelle C. Buri; Wolfgang Weninger; Eva M. Putz; Miller Huang; Ruth Ladenstein; Peter W. Andrews; Ivana Barbaric; George D. Cresswell; Helen E. Bryant; Martin Distel; Louis Chesler; Sabine Taschner-Mandl; Matthias Farlik; Anestis Tsakiridis; Florian Halbritter
Source
Nature Communications, Vol 15, Iss 1, Pp 1-25 (2024)
Subject
Language
English
ISSN
2041-1723
Abstract
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.