Somatic mutations and single cell transcriptomes reveal the root of malignant rhabdoid tumours
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.
- 30 samples
- DAC: EGAC00001000000
- Technologies: HiSeq X Ten, Illumina HiSeq 4000, Illumina NovaSeq 6000, NextSeq 500
- PUB DUO:0000019 (version: 2021-02-23)publication requiredThis data use modifier indicates that requestor agrees to make results of studies using the data available to the larger scientific community.
- US DUO:0000026 (version: 2021-02-23)user specific restrictionThis data use modifier indicates that use is limited to use by approved users.
- IS DUO:0000028 (version: 2021-02-23)institution specific restrictionThis data use modifier indicates that use is limited to use within an approved institution.
- GRU DUO:0000042 (version: 2021-02-23)general research useThis data use permission indicates that use is allowed for general research use for any research purpose.
Wellcome Trust Sanger Institute Cancer Genome Group Data Sharing Policy
Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.
| Study ID | Study Title | Study Type |
|---|---|---|
| EGAS00001002486 | Cancer Genomics | |
| EGAS00001003386 | Cancer Genomics |
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