Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis

Zaili Luo, Mingyang Xia, Wei Shi, Chuntao Zhao, Jiajia Wang, Dazhuan Xin, Xinran Dong, Yu Xiong, Feng Zhang, Kalen Berry, Sean Ogurek, Xuezhao Liu, Rohit Rao, Rui Xing, Lai Man Natalie Wu, Siying Cui, Lingli Xu, Yifeng Lin, Wenkun Ma, Shuaiwei TianQi Xie, Li Zhang, Mei Xin, Xiaotao Wang, Feng Yue, Haizi Zheng, Yaping Liu, Charles B. Stevenson, Peter de Blank, John P. Perentesis, Richard J. Gilbertson, Hao Li, Jie Ma, Wenhao Zhou, Michael D. Taylor, Q. Richard Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3–5 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.

Original languageEnglish (US)
Pages (from-to)787-794
Number of pages8
JournalNature
Volume612
Issue number7941
DOIs
StatePublished - Dec 22 2022

Funding

We thank K. J. Millen and E. Hurlock for comments, suggestions and edits. We appreciate the technical support from A. E. Bayat. This study was supported in part by grants from the Cincinnati Research Foundation ARC award, CancerFree Kids Foundation, Pray-Hope-Believe Foundation, TeamConnor Childhood Cancer Foundation, and CureStartsNow Foundation to Q.R.L.

ASJC Scopus subject areas

  • General

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