Dataset

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

Dataset ID Technology Samples
EGAD00001006296 HiSeq X Ten,Illumina HiSeq 4000,Illumina NovaSeq 6000,NextSeq 500 30

Dataset Description

Like many childhood cancers, malignant rhabdoid tumours (MRT) are thought to arise from aberrant foetal development. Although MRT predominantly exhibit a mesenchymal phenotype, it has been suggested that the foetal root of MRT lies in neural crest development. Here, we combine phylogenetic analyses of MRT, single cell mRNA assays, and functional experiments in patient-derived MRT organoids, to define the embryological origin of MRT and explore therapeutic avenues that may drive MRT differentiation. Phylogenetic analyses from the distribution of somatic mutations revealed that MRT were related to neural crest-derived, but not to mesodermal tissues, providing direct evidence of the neural crest origin of MRT in humans. In MRT organoids, reversal of the principal driver event underpinning MRT, SMARCB1 loss, induced differentiation along mesenchymal pathways. Together, these findings placed MRT cells on a developmental trajectory of neural crest to mesenchyme conversion, and defined the transcriptional changes underpinning MRT differentiation. Searching perturbation databases for agents that mimic these mRNA changes, we identified HDAC and mTOR inhibition as potential differentiation agents. Treatment of MRT organoids with this drug combination induced proliferation arrest with transcriptional changes akin to SMARCB1 re-expression. Our study defines the embryological root of MRT and proposes a differentiation treatment for this often fatal childhood cancer.

Data Use Conditions

IS PUB US

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Label Code Version Modifier
general research use DUO:0000042 2021-02-23
institution specific restriction DUO:0000028 2021-02-23
publication required DUO:0000019 2021-02-23
user specific restriction DUO:0000026 2021-02-23