Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

• Published in: Nature communications Vol. 12; no. 1; pp. 1407 - 11
• Main Authors: Custers, Lars, Khabirova, Eleonora, Coorens, Tim H. H., Oliver, Thomas R. W., Calandrini, Camilla, Young, Matthew D., Vieira Braga, Felipe A., Ellis, Peter, Mamanova, Lira, Segers, Heidi, Maat, Arie, Kool, Marcel, Hoving, Eelco W., van den Heuvel-Eibrink, Marry M., Nicholson, James, Straathof, Karin, Hook, Liz, de Krijger, Ronald R., Trayers, Claire, Allinson, Kieren, Behjati, Sam, Drost, Jarno
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 38/23; 38/39; 38/91; 45; 631/1647/2217; 631/1647/767/70; 631/337/2019; 631/67/1678; Cancer; Cell differentiation; Cell Differentiation - genetics; Children; DNA Methylation; Drug Screening Assays, Antitumor; Ectoderm; Embryogenesis; Fetuses; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Humanities and Social Sciences; Humans; Mesenchyme; multidisciplinary; Mutation; Neural crest; Neural Crest - pathology; Organoids; Phylogenetics; Phylogeny; Rhabdoid Tumor - drug therapy; Rhabdoid Tumor - genetics; Rhabdoid Tumor - pathology; Schwann cells; Science; Science (multidisciplinary); Single-Cell Analysis; SMARCB1 Protein - genetics; Tissue Culture Techniques - methods; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; Transcription; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21675-6

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. Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.