TY  - JOUR
AU  - Custers, Lars
AU  - Khabirova, Eleonora
AU  - Coorens, Tim H H
AU  - Oliver, Thomas R W
AU  - Calandrini, Camilla
AU  - Young, Matthew D
AU  - Vieira Braga, Felipe A
AU  - Ellis, Peter
AU  - Mamanova, Lira
AU  - Segers, Heidi
AU  - Maat, Arie
AU  - Kool, Marcel
AU  - Hoving, Eelco W
AU  - van den Heuvel-Eibrink, Marry M
AU  - Nicholson, James
AU  - Straathof, Karin
AU  - Hook, Liz
AU  - de Krijger, Ronald R
AU  - Trayers, Claire
AU  - Allinson, Kieren
AU  - Behjati, Sam
AU  - Drost, Jarno
TI  - Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours.
JO  - Nature Communications
VL  - 12
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2021-00542
SP  - 1407
PY  - 2021
AB  - Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies.
LB  - PUB:(DE-HGF)16
C6  - pmid:33658498
DO  - DOI:10.1038/s41467-021-21675-6
UR  - https://inrepo02.dkfz.de/record/167780
ER  -