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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.

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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

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00004149824 cram 3.9 GB
EGAF00004149825 cram 4.3 GB
EGAF00004149826 cram 3.5 GB
EGAF00004149827 cram 4.6 GB
EGAF00004149828 cram 3.9 GB
EGAF00004149829 cram 4.2 GB
EGAF00004149830 cram 3.5 GB
EGAF00004149831 cram 4.6 GB
EGAF00004149832 cram 3.9 GB
EGAF00004149833 cram 4.2 GB
EGAF00004149834 cram 3.5 GB
EGAF00004149835 cram 4.6 GB
EGAF00004149836 cram 3.9 GB
EGAF00004149837 cram 4.2 GB
EGAF00004149838 cram 3.5 GB
EGAF00004149839 cram 4.6 GB
EGAF00004149840 cram 3.9 GB
EGAF00004149841 cram 4.2 GB
EGAF00004149842 cram 3.5 GB
EGAF00004149843 cram 4.6 GB
EGAF00004149844 cram 3.9 GB
EGAF00004149845 cram 4.3 GB
EGAF00004149846 cram 3.5 GB
EGAF00004149847 cram 4.6 GB
EGAF00004149848 cram 3.9 GB
EGAF00004149849 cram 4.2 GB
EGAF00004149850 cram 3.5 GB
EGAF00004149851 cram 4.6 GB
EGAF00004149852 cram 3.9 GB
EGAF00004149853 cram 4.2 GB
EGAF00004149854 cram 3.5 GB
EGAF00004149855 cram 4.6 GB
EGAF00004149856 cram 15.4 GB
EGAF00004149857 cram 11.6 GB
EGAF00004149858 cram 11.8 GB
EGAF00004149859 cram 15.3 GB
EGAF00004149860 cram 11.4 GB
EGAF00004149861 cram 11.5 GB
EGAF00004149862 cram 15.5 GB
EGAF00004149863 cram 11.6 GB
EGAF00004149864 cram 11.7 GB
EGAF00004149865 cram 11.3 GB
EGAF00004149866 cram 9.6 GB
EGAF00004149867 cram 11.7 GB
EGAF00004149868 cram 11.1 GB
EGAF00004149869 cram 8.4 GB
EGAF00004149870 cram 9.2 GB
EGAF00004149871 cram 8.7 GB
EGAF00004149872 cram 11.0 GB
EGAF00004149873 cram 9.0 GB
EGAF00004149874 cram 9.6 GB
EGAF00004149875 cram 9.4 GB
EGAF00004149876 cram 14.0 GB
EGAF00004149877 cram 13.1 GB
EGAF00004149878 cram 11.4 GB
EGAF00004149879 cram 9.7 GB
EGAF00004149880 cram 11.7 GB
EGAF00004149881 cram 11.2 GB
EGAF00004149882 cram 8.4 GB
EGAF00004149883 cram 9.3 GB
EGAF00004149884 cram 8.7 GB
EGAF00004149885 cram 11.0 GB
EGAF00004149886 cram 9.1 GB
EGAF00004149887 cram 9.6 GB
EGAF00004149888 cram 9.4 GB
EGAF00004149889 cram 14.1 GB
EGAF00004149890 cram 13.1 GB
EGAF00004149891 cram 32.8 GB
EGAF00004149892 cram 4.3 GB
EGAF00004149893 cram 4.8 GB
EGAF00004149894 cram 5.9 GB
EGAF00004149895 cram 4.3 GB
EGAF00004149896 cram 4.1 GB
EGAF00004149897 cram 5.6 GB
EGAF00004149898 cram 5.6 GB
EGAF00004149899 cram 3.8 GB
EGAF00004149900 cram 6.3 GB
EGAF00004149901 cram 5.8 GB
EGAF00004149902 cram 4.6 GB
EGAF00004149903 cram 5.4 GB
EGAF00004177329 bam 2.2 GB
EGAF00004177330 bam 5.3 GB
EGAF00004177331 bam 3.6 GB
EGAF00004177332 bam 8.9 GB
EGAF00004177333 bam 6.9 GB
EGAF00004177334 bam 11.4 GB
86 Files (649.6 GB)