Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis.

Autor: Luo Z; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Xia M; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Fudan University, Shanghai, China., Shi W; Department of Neurosurgery, Children's Hospital of Fudan University, Shanghai, China., Zhao C; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Wang J; Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Xin D; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Dong X; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Fudan University, Shanghai, China., Xiong Y; Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China., Zhang F; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Berry K; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Ogurek S; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Liu X; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Rao R; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Xing R; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Wu LMN; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Cui S; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Fudan University, Shanghai, China., Xu L; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Fudan University, Shanghai, China., Lin Y; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Fudan University, Shanghai, China., Ma W; Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Tian S; Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Xie Q; School of Life Sciences, Westlake University, Hangzhou, China., Zhang L; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Xin M; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Wang X; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA., Yue F; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA., Zheng H; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Liu Y; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Stevenson CB; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., de Blank P; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Perentesis JP; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Gilbertson RJ; Cancer Research UK Cambridge Centre, CRUK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Li H; Department of Neurosurgery, Children's Hospital of Fudan University, Shanghai, China. lihao7272@163.com., Ma J; Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. majie@xinhuamed.com.cn., Zhou W; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Fudan University, Shanghai, China. zhouwenhao@fudan.edu.cn., Taylor MD; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada., Lu QR; Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Richard.Lu@cchmc.org.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Dec; Vol. 612 (7941), pp. 787-794. Date of Electronic Publication: 2022 Nov 30.
DOI: 10.1038/s41586-022-05487-2
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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