Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours.
Cell Differentiation
/ genetics
DNA Methylation
Drug Screening Assays, Antitumor
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
/ drug effects
Histone Deacetylase Inhibitors
/ pharmacology
Humans
Mutation
Neural Crest
/ pathology
Phylogeny
Rhabdoid Tumor
/ drug therapy
SMARCB1 Protein
/ genetics
Single-Cell Analysis
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Tissue Culture Techniques
/ methods
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 03 2021
03 03 2021
Historique:
received:
01
06
2020
accepted:
05
02
2021
entrez:
4
3
2021
pubmed:
5
3
2021
medline:
19
3
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33658498
doi: 10.1038/s41467-021-21675-6
pii: 10.1038/s41467-021-21675-6
pmc: PMC7930245
doi:
Substances chimiques
Histone Deacetylase Inhibitors
0
SMARCB1 Protein
0
SMARCB1 protein, human
0
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1407Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
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