Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis.
Zaili LuoMingyang XiaWei ShiChuntao ZhaoJiajia WangDazhuan XinXinran DongYu XiongFeng ZhangKalen BerrySean OgurekXuezhao LiuRohit RaoRui XingLai Man Natalie WuSiying CuiLingli XuYifeng LinWenkun MaShuaiwei TianQi XieLi ZhangMei XinXiao-Tao WangFeng YueHaizi ZhengYaping LiuCharles B StevensonPeter M K de BlankJohn P PerentesisRichard J GilbertsonHao LiJie MaWen-Hao ZhouMichael D TaylorQing Richard LuPublished in: Nature (2022)
Medulloblastoma (MB) is the most common malignant childhood brain tumour 1,2 , yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella 3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.
Keyphrases
- single cell
- transcription factor
- rna seq
- endothelial cells
- high throughput
- induced pluripotent stem cells
- cancer therapy
- neural stem cells
- squamous cell carcinoma
- small cell lung cancer
- stem cells
- pluripotent stem cells
- gene expression
- cell fate
- dna methylation
- randomized controlled trial
- study protocol
- multiple sclerosis
- blood brain barrier
- copy number
- data analysis
- cerebral ischemia