Mapping pediatric brain tumors to their origins in the developing cerebellum
Konstantin Okonechnikov
(1, 2, 3)
,
Piyush Joshi
(1, 2, 3)
,
Mari Sepp
(4)
,
Kevin Leiss
(4)
,
Ioannis Sarropoulos
(4)
,
Florent Murat
(4)
,
Martin Sill
(1, 2, 3)
,
Pengbo Beck
(1, 2, 3)
,
Kenneth Chun-Ho Chan
(1, 2, 3)
,
Andrey Korshunov
(1, 2, 5)
,
Felix Sahm
(1, 2, 5)
,
Maximilian Deng
(1, 2)
,
Dominik Sturm
(1, 2, 5)
,
John Desisto
(6)
,
Andrew Donson
(6)
,
Nicholas Foreman
(6, 7)
,
Adam Green
(6, 7)
,
Giles Robinson
(8)
,
Brent Orr
(8)
,
Qingsong Gao
(8)
,
Emily Darrow
(8)
,
Jennifer Hadley
(8)
,
Paul Northcott
(8)
,
Johannes Gojo
(1, 2, 3, 9)
,
Marina Ryzhova
(10)
,
Daisuke Kawauchi
(11)
,
Volker Hovestadt
(12, 13)
,
Mariella Filbin
(12, 13)
,
Andreas Von Deimling
(1, 2, 5)
,
Marc Zuckermann
(1, 2, 3)
,
Kristian Pajtler
(1, 2)
,
Marcel Kool
(1, 2, 3, 14)
,
David T.W. Jones
(1, 2)
,
Natalie Jäger
(1, 2, 3)
,
Lena Kutscher
(1, 2)
,
Henrik Kaessmann
(4)
,
Stefan Pfister
(1, 2, 3, 5)
1
KITZ -
Hopp Children's Cancer Center Heidelberg [Heidelber, Germany]
2 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
3 DKTK - German Cancer Consortium [Heidelberg]
4 ZMBH - Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany]
5 Heidelberg University Hospital [Heidelberg]
6 University of Colorado School of Medicine
7 Children’s Hospital Colorado
8 St Jude Children's Research Hospital
9 Medizinische Universität Wien = Medical University of Vienna
10 NNBNI - NN Burdenko Neurosurgical Institute
11 NCNP - National Institute of Neuroscience
12 Dana-Farber Cancer Institute [Boston]
13 BROAD INSTITUTE - Broad Institute of MIT and Harvard
14 Princess Máxima Center for Pediatric Oncology [Utrecht, Netherlands]
2 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
3 DKTK - German Cancer Consortium [Heidelberg]
4 ZMBH - Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany]
5 Heidelberg University Hospital [Heidelberg]
6 University of Colorado School of Medicine
7 Children’s Hospital Colorado
8 St Jude Children's Research Hospital
9 Medizinische Universität Wien = Medical University of Vienna
10 NNBNI - NN Burdenko Neurosurgical Institute
11 NCNP - National Institute of Neuroscience
12 Dana-Farber Cancer Institute [Boston]
13 BROAD INSTITUTE - Broad Institute of MIT and Harvard
14 Princess Máxima Center for Pediatric Oncology [Utrecht, Netherlands]
Mari Sepp
- Fonction : Auteur
- PersonId : 819723
- ORCID : 0000-0003-1733-8385
Kevin Leiss
- Fonction : Auteur
- PersonId : 819729
- ORCID : 0000-0002-5955-6076
Ioannis Sarropoulos
- Fonction : Auteur
- PersonId : 819730
- ORCID : 0000-0002-2242-0562
Florent Murat
- Fonction : Auteur
- PersonId : 751486
- IdHAL : florent-murat
- ORCID : 0000-0003-2116-2511
Marcel Kool
- Fonction : Auteur
- PersonId : 779773
- ORCID : 0000-0002-6557-5468
Lena Kutscher
- Fonction : Auteur
- PersonId : 812666
- ORCID : 0000-0002-1130-4582
Henrik Kaessmann
- Fonction : Auteur
- PersonId : 804552
- ORCID : 0000-0001-7563-839X
Stefan Pfister
- Fonction : Auteur
- PersonId : 769435
- ORCID : 0000-0002-5447-5322
Résumé
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 tissues 1,2 , a potentially imperfect approach due to spatio-temporal gene expression differences between species 3 . 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”.