Mapping pediatric brain tumors to their origins in the developing cerebellum
Konstantin Okonechnikov
(1, 2, 3)
,
Piyush Joshi
(1, 2, 3)
,
Mari Sepp
(1, 2, 3, 4)
,
Kevin Leiss
(4)
,
Ioannis Sarropoulos
(4)
,
Florent Murat
(5, 4)
,
Martin Sill
(1)
,
Pengbo Beck
(1, 2, 3)
,
Kenneth Chun-Ho Chan
(1, 2, 3)
,
Andrey Korshunov
(1, 3, 6)
,
Felix Sahm
(1, 3, 6)
,
Maximilian Deng
(1, 3)
,
Dominik Sturm
(1, 3, 6)
,
John Desisto
(7)
,
Andrew Donson
(7)
,
Nicholas Foreman
(7, 8)
,
Adam Green
(7, 8)
,
Giles Robinson
(9)
,
Brent Orr
(9)
,
Qingsong Gao
(9)
,
Emily Darrow
(9)
,
Jennifer Hadley
(9)
,
Paul Northcott
(9)
,
Johannes Gojo
(1, 2, 3, 10, 11)
,
Daisuke Kawauchi
(12)
,
Volker Hovestadt
(13, 14)
,
Mariella Filbin
(13, 14)
,
Andreas von Deimling
(1, 3, 6)
,
Marc Zuckermann
(1, 2, 3)
,
Kristian Pajtler
(1, 2, 3)
,
Marcel Kool
(1, 2, 3, 15)
,
David Jones
(1, 3)
,
Natalie Jäger
(1, 2, 3)
,
Lena Kutscher
(1, 3)
,
Henrik Kaessmann
(4)
,
Stefan Pfister
(1, 2, 3)
1
DKFZ -
German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
2 DKTK - German Cancer Consortium [Heidelberg]
3 KITZ - Hopp Children's Cancer Center Heidelberg [Heidelber, Germany]
4 ZMBH - Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany]
5 LPGP - Laboratoire de Physiologie et Génomique des Poissons = Fish Physiology and Genomics Institute
6 Heidelberg University Hospital [Heidelberg]
7 University of Colorado [Denver]
8 Children’s Hospital Colorado
9 St Jude Children's Research Hospital
10 Medizinische Universität Wien = Medical University of Vienna
11 NNBNI - NN Burdenko Neurosurgical Institute
12 NCNP - National Institute of Neuroscience Tokyo
13 Dana-Farber Cancer Institute [Boston]
14 BROAD INSTITUTE - Broad Institute of MIT and Harvard
15 Princess Máxima Center for Pediatric Oncology
2 DKTK - German Cancer Consortium [Heidelberg]
3 KITZ - Hopp Children's Cancer Center Heidelberg [Heidelber, Germany]
4 ZMBH - Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany]
5 LPGP - Laboratoire de Physiologie et Génomique des Poissons = Fish Physiology and Genomics Institute
6 Heidelberg University Hospital [Heidelberg]
7 University of Colorado [Denver]
8 Children’s Hospital Colorado
9 St Jude Children's Research Hospital
10 Medizinische Universität Wien = Medical University of Vienna
11 NNBNI - NN Burdenko Neurosurgical Institute
12 NCNP - National Institute of Neuroscience Tokyo
13 Dana-Farber Cancer Institute [Boston]
14 BROAD INSTITUTE - Broad Institute of MIT and Harvard
15 Princess Máxima Center for Pediatric Oncology
Florent Murat
- Fonction : Auteur
- PersonId : 751486
- IdHAL : florent-murat
- ORCID : 0000-0003-2116-2511
Martin Sill
- Fonction : Auteur
- PersonId : 1275855
- ORCID : 0000-0001-7616-7665
Adam Green
- Fonction : Auteur
- PersonId : 1275856
- ORCID : 0000-0002-4469-2358
Johannes Gojo
- Fonction : Auteur
Stefan Pfister
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- Fonction : Auteur correspondant
- PersonId : 769435
- ORCID : 0000-0002-5447-5322
Connectez-vous pour contacter l'auteur
Résumé
Background 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. Methods 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. Results 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. Conclusion 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”.