Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis.

in Nature by 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 de Blank, John P Perentesis, Richard J Gilbertson, Hao Li, Jie Ma, Wenhao Zhou, Michael D Taylor, Q Richard Lu

TLDR

  • This study used single-cell profiling to identify a new population of transitional cerebellar progenitors that may be predictive of disease prognosis and potential therapeutic vulnerabilities in group 3 medulloblastoma.

Abstract

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

Overview

  • The study focuses on understanding the origin of the most aggressive form of medulloblastoma (MB), a common malignant childhood brain tumor.
  • The researchers used single-cell profiling of human fetal cerebella to establish a reference map of hierarchical cellular states in MBs.
  • The study aimed to identify potential therapeutic vulnerabilities by understanding the regulatory networks and cellular states in MBs.

Comparative Analysis & Findings

  • The researchers identified a unique transitional cerebellar progenitor population that connects neural stem cells to neuronal lineages in developing fetal cerebella.
  • The transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumors.
  • Genomic and Hi-C profiling revealed de novo long-range chromatin loops that regulate the MYC oncogene in group 3 MBs, which was correlated with clinical prognosis.

Implications and Future Directions

  • The study highlights the importance of understanding the regulatory circuitries underlying tumour cell states and oncogenesis in MBs.
  • The finding of transitional progenitor regulators and their correlations with clinical prognosis has potential therapeutic implications for group 3 MBs.
  • Future studies could focus on targeting these regulators to inhibit MYC expression and MYC-driven group 3 MB growth.
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