Mapping pediatric brain tumors to their origins in the developing cerebellum
Mapping pediatric brain tumors to their origins in the developing cerebellum
Understanding the cellular origins of childhood brain tumors is key for discovering novel tumor-specific therapeutic targets. Previous strategies mapping cellular origins typically involved comparing human tumors to murine embryonal tissues1,2, a potentially imperfect approach due to spatio-temporal gene expression differences between species3. Here we use an unprecedented single-nucleus atlas of the developing human cerebellum (Sepp, Leiss, et al) and extensive bulk and single-cell transcriptome tumor data to map their cellular origins with focus on three most common pediatric brain tumors – pilocytic astrocytoma, ependymoma, and medulloblastoma. Using custom bioinformatics approaches, we postulate the astroglial and glial lineages as the origins for posterior fossa ependymomas and radiation-induced gliomas (secondary tumors after medulloblastoma treatment), respectively. Moreover, we confirm that SHH, Group3 and Group4 medulloblastomas stem from granule cell/unipolar brush cell lineages, whereas we propose pilocytic astrocytoma to originate from the oligodendrocyte lineage. We also identify genes shared between the cerebellar lineage of origin and corresponding tumors, and genes that are tumor specific; both gene sets represent promising therapeutic targets. As a common feature among most cerebellar tumors, we observed compositional heterogeneity in terms of similarity to normal cells, suggesting that tumors arise from or differentiate into multiple points along the cerebellar “lineage of origin”.
Ryzhova Marina、Gojo Johannes、Hovestadt Volker、Kutscher Lena M.、Okonechnikov Konstantin、Joshi Piyush、Sarropoulos Ioannis、Murat Florent、Beck Pengbo、Donson Andrew M.、Green Adam L.、Robinson Giles、Orr Brent A.、Gao Qingsong、Jones David T.W.、Sill Martin、Pajtler Kristian W.、Kawauchi Daisuke、Filbin Mariella G.、Sahm Felix、Deimling Andreas von、Leiss Kevin、Sturm Dominik、Sepp Mari、Northcott Paul A.、Deng Maximilian Y.、Zuckermann Marc、Chan Kenneth Chun-Ho、DeSisto John、Darrow Emily、Kool Marcel、Korshunov Andrey、J?ger Natalie、Pfister Stefan M.、Hadley Jennifer L.、Foreman Nicholas K.、Kaessmann Henrik
Department of Neuropathology, NN Burdenko Neurosurgical InstituteHopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)||Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of ViennaDepartment of Pediatric Oncology, Dana-Farber Boston Children?ˉs Cancer and Blood Disorders Center||Broad Institute of Harvard and MITHopp Children?ˉs Cancer Center (KiTZ)||Developmental Origins of Pediatric Cancer Group, German Cancer Research Center (DKFZ)Hopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Hopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)||Developmental Origins of Pediatric Cancer Group, German Cancer Research Center (DKFZ)Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH AllianceCenter for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH AllianceHopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Morgan Adams Foundation Pediatric Brain Tumor Research Program, University of Colorado School of MedicineMorgan Adams Foundation Pediatric Brain Tumor Research Program, University of Colorado School of Medicine||Children?ˉs Hospital ColoradoDepartment of Oncology, St Jude Children?ˉs Research HospitalDepartment of Pathology, St Jude Children?ˉs Research HospitalDepartment of Pathology, St Jude Children?ˉs Research Hospital||Department of Developmental Neurobiology, St Jude Children?ˉs Research HospitalHopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ)Hopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Hopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)||Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNPDepartment of Pediatric Oncology, Dana-Farber Boston Children?ˉs Cancer and Blood Disorders Center||Broad Institute of Harvard and MITHopp Children?ˉs Cancer Center (KiTZ)||Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)||Department of Neuropathology, Institute of Pathology, Heidelberg University HospitalHopp Children?ˉs Cancer Center (KiTZ)||Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)||Department of Neuropathology, Institute of Pathology, Heidelberg University HospitalCenter for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH AllianceHopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ)||Department of Pediatric Hematology and Oncology, Heidelberg University HospitalCenter for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH AllianceDepartment of Developmental Neurobiology, St Jude Children?ˉs Research HospitalHopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ)Hopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Hopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Morgan Adams Foundation Pediatric Brain Tumor Research Program, University of Colorado School of MedicineDepartment of Developmental Neurobiology, St Jude Children?ˉs Research HospitalHopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)||Princess M¨￠xima Center for Pediatric OncologyHopp Children?ˉs Cancer Center (KiTZ)||Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)||Department of Neuropathology, Institute of Pathology, Heidelberg University HospitalHopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Hopp Children?ˉs Cancer Center (KiTZ)||Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)||Department of Pediatric Hematology and Oncology, Heidelberg University HospitalDepartment of Developmental Neurobiology, St Jude Children?ˉs Research HospitalMorgan Adams Foundation Pediatric Brain Tumor Research Program, University of Colorado School of Medicine||Children?ˉs Hospital ColoradoCenter for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
肿瘤学基础医学神经病学、精神病学
Ryzhova Marina,Gojo Johannes,Hovestadt Volker,Kutscher Lena M.,Okonechnikov Konstantin,Joshi Piyush,Sarropoulos Ioannis,Murat Florent,Beck Pengbo,Donson Andrew M.,Green Adam L.,Robinson Giles,Orr Brent A.,Gao Qingsong,Jones David T.W.,Sill Martin,Pajtler Kristian W.,Kawauchi Daisuke,Filbin Mariella G.,Sahm Felix,Deimling Andreas von,Leiss Kevin,Sturm Dominik,Sepp Mari,Northcott Paul A.,Deng Maximilian Y.,Zuckermann Marc,Chan Kenneth Chun-Ho,DeSisto John,Darrow Emily,Kool Marcel,Korshunov Andrey,J?ger Natalie,Pfister Stefan M.,Hadley Jennifer L.,Foreman Nicholas K.,Kaessmann Henrik.Mapping pediatric brain tumors to their origins in the developing cerebellum[EB/OL].(2025-03-28)[2025-07-01].https://www.biorxiv.org/content/10.1101/2021.12.19.473154.点此复制
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