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 Tian, Qi Xie, Li Zhang, Mei Xin, Xiaotao Wang, Feng Yue, Haizi Zheng, Yaping Liu, Charles B. Stevenson, Peter Blank, John P. Perentesis, Richard J. Gilbertson, Hao Li (), Jie Ma (), Wenhao Zhou (), Michael D. Taylor and Q. Richard Lu ()
Additional contact information
Zaili Luo: Cincinnati Children’s Hospital Medical Center
Mingyang Xia: Children’s Hospital of Fudan University, Fudan University
Wei Shi: Children’s Hospital of Fudan University
Chuntao Zhao: Cincinnati Children’s Hospital Medical Center
Jiajia Wang: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Dazhuan Xin: Cincinnati Children’s Hospital Medical Center
Xinran Dong: Children’s Hospital of Fudan University, Fudan University
Yu Xiong: Obstetrics and Gynecology Hospital of Fudan University
Feng Zhang: Cincinnati Children’s Hospital Medical Center
Kalen Berry: Cincinnati Children’s Hospital Medical Center
Sean Ogurek: Cincinnati Children’s Hospital Medical Center
Xuezhao Liu: Cincinnati Children’s Hospital Medical Center
Rohit Rao: Cincinnati Children’s Hospital Medical Center
Rui Xing: Cincinnati Children’s Hospital Medical Center
Lai Man Natalie Wu: Cincinnati Children’s Hospital Medical Center
Siying Cui: Children’s Hospital of Fudan University, Fudan University
Lingli Xu: Children’s Hospital of Fudan University, Fudan University
Yifeng Lin: Children’s Hospital of Fudan University, Fudan University
Wenkun Ma: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Shuaiwei Tian: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Qi Xie: Westlake University
Li Zhang: Cincinnati Children’s Hospital Medical Center
Mei Xin: Cincinnati Children’s Hospital Medical Center
Xiaotao Wang: Feinberg School of Medicine Northwestern University
Feng Yue: Feinberg School of Medicine Northwestern University
Haizi Zheng: Cincinnati Children’s Hospital Medical Center
Yaping Liu: Cincinnati Children’s Hospital Medical Center
Charles B. Stevenson: Cincinnati Children’s Hospital Medical Center
Peter Blank: Cincinnati Children’s Hospital Medical Center
John P. Perentesis: Cincinnati Children’s Hospital Medical Center
Richard J. Gilbertson: Cancer Research UK Cambridge Centre, CRUK Cambridge Institute, Li Ka Shing Centre
Hao Li: Children’s Hospital of Fudan University
Jie Ma: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Wenhao Zhou: Children’s Hospital of Fudan University, Fudan University
Michael D. Taylor: The Hospital for Sick Children
Q. Richard Lu: Cincinnati Children’s Hospital Medical Center

Nature, 2022, vol. 612, issue 7941, 787-794

Abstract: 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.

Date: 2022
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05487-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:612:y:2022:i:7941:d:10.1038_s41586-022-05487-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05487-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().