TY - JOUR
T1 - Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours
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
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/3/3
Y1 - 2021/3/3
N2 - 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.
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.
KW - Cell Differentiation/genetics
KW - DNA Methylation
KW - Drug Screening Assays, Antitumor
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Histone Deacetylase Inhibitors/pharmacology
KW - Humans
KW - Mutation
KW - Neural Crest/pathology
KW - Phylogeny
KW - Rhabdoid Tumor/drug therapy
KW - SMARCB1 Protein/genetics
KW - Single-Cell Analysis
KW - TOR Serine-Threonine Kinases/antagonists & inhibitors
KW - Tissue Culture Techniques/methods
UR - http://www.scopus.com/inward/record.url?scp=85101897479&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-21675-6
DO - 10.1038/s41467-021-21675-6
M3 - Article
C2 - 33658498
SN - 2041-1723
VL - 12
SP - 1407
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1407
ER -