A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations.
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Date
2024-05-03Author
Saldana-Guerrero, IM
Montano-Gutierrez, LF
Boswell, K
Hafemeister, C
Poon, E
Shaw, LE
Stavish, D
Lea, RA
Wernig-Zorc, S
Bozsaky, E
Fetahu, IS
Zoescher, P
Pötschger, U
Bernkopf, M
Wenninger-Weinzierl, A
Sturtzel, C
Souilhol, C
Tarelli, S
Shoeb, MR
Bozatzi, P
Rados, M
Guarini, M
Buri, MC
Weninger, W
Putz, EM
Huang, M
Ladenstein, R
Andrews, PW
Barbaric, I
Cresswell, GD
Bryant, HE
Distel, M
Chesler, L
Taschner-Mandl, S
Farlik, M
Tsakiridis, A
Halbritter, F
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Humans
Neuroblastoma
Neural Crest
Female
DNA Copy Number Variations
Cell Differentiation
N-Myc Proto-Oncogene Protein
Chromosome Aberrations
Human Embryonic Stem Cells
Transcriptome
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Research team
Paediatric Tumour Biology
Language
eng
Date accepted
2024-04-15
License start date
2024-05-03
Citation
Nature Communications, 2024, 15 (1), pp. 3745 -
Publisher
NATURE PORTFOLIO