TY  - JOUR
AU  - Okonechnikov, Konstantin
AU  - Joshi, Piyush Kumar
AU  - Sepp, Mari
AU  - Leiss, Kevin
AU  - Sarropoulos, Ioannis
AU  - Murat, Florent
AU  - Sill, Martin
AU  - Beck, Pengbo
AU  - Chan, Kenneth Chun-Ho
AU  - Korshunov, Andrey
AU  - Sahm, Felix
AU  - Deng, Maximilian Yuanzhe
AU  - Sturm, Dominik
AU  - DeSisto, John
AU  - Donson, Andrew M
AU  - Foreman, Nicholas K
AU  - Green, Adam L
AU  - Robinson, Giles
AU  - Orr, Brent A
AU  - Gao, Qingsong
AU  - Darrow, Emily
AU  - Hadley, Jennifer L
AU  - Northcott, Paul A
AU  - Gojo, Johannes
AU  - Kawauchi, Daisuke
AU  - Hovestadt, Volker
AU  - Filbin, Mariella G
AU  - von Deimling, Andreas
AU  - Zuckermann, Marc
AU  - Pajtler, Kristian
AU  - Kool, Marcel
AU  - Jones, David
AU  - Jäger, Natalie
AU  - Kutscher, Lena
AU  - Kaessmann, Henrik
AU  - Pfister, Stefan
TI  - Mapping pediatric brain tumors to their origins in the developing cerebellum.
JO  - Neuro-Oncology
VL  - 25
IS  - 10
SN  - 1522-8517
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2023-01578
SP  - 1895-1909
PY  - 2023
N1  - DKFZ-ZMBH Alliance / #EA:B062#EA:B430#LA:B062#LA:B430# / 2023 Oct 3;25(10):1895-1909
AB  - Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the three most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas.We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176,645 cells as a reference for an in-depth comparison to 4,416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques.We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study.Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar 'lineage of origin'.
KW  - cerebellum (Other)
KW  - ependymoma (Other)
KW  - medulloblastoma (Other)
KW  - pilocytic astrocytoma (Other)
KW  - radiation-induced glioma (Other)
KW  - tumor origin (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37534924
DO  - DOI:10.1093/neuonc/noad124
UR  - https://inrepo02.dkfz.de/record/277922
ER  -