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A biobank of patient-derived pediatric brain tumor models

Nature Medicine volume 24, pages 1752–1761 (2018)Cite this article

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Abstract

Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children’s Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.

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Fig. 1: PDOX of pediatric brain tumors.
Fig. 2: Histology and immunohistochemistry are conserved in PDOX.
Fig. 3: Molecular subgrouping of PDOX models and cell lines.
Fig. 4: Molecular characterization of PDOX models and cell lines.
Fig. 5: Molecular fidelity of PDOX models.
Fig. 6: Preclinical evaluation of targeted therapeutics shows differential response to therapy based on molecular drivers.

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Data availability

PDOX lines described here, as well as additional lines being developed and characterized, are catalogued online and shared with other researchers at the Brain Tumor Resource Laboratory (http://www.btrl.org). In addition, an online summary of each model and interactive access to the molecular and histopathological data can be found in the R2 PDX Explorer (http://www.r2platform.com/pdxexplorer). Short-read sequencing data are available at the European Genome-phenome Archive (http://www.ebi.ac.uk/ega/), hosted by the European Bioinformatics Institute, under accession EGAS00001002536. Methylation and gene expression data have been deposited in the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo) under accessions GSE99994 and GSE99961.

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Acknowledgements

We are grateful to the patients and families who consented to provide tissue to generate these resources. We thank A. Richards, M. Merrill, D. Acorn, M. Biery, A. Wittmann, and L. Sieber for experimental contributions. We thank the DKFZ Genomics and Proteomics Core Facility, DKFZ Heidelberg, Germany, and the AMC Department of Oncogenomics, Amsterdam, The Netherlands, for performing high-throughput sequencing and microarray analyses to a very high standard. We also thank the DKFZ data management group, especially I. Scholz, for their excellent support in processing the sequencing data, and Z. Gu for the defuse pipeline. We thank X.-N. Li, R. J. Wechsler-Reya, and T. Milde for allowing us to list their PDOX lines on our websites. This work was supported by NIH 1U10CA180886-01 (J.M.O.), NIH 1R01CA155360 (J.M.O.), NIH R01 CA114567 (J.M.O.), the Seattle Run of Hope, the Seattle Children’s Brain Tumor Research Endowment, the Dutch Cancer Foundations KWF (2010-4713) (M.K.) and KIKA (90) (M.K.), Deutsche Krebshilfe (111537) (S.M.P., M.K.), BMBF (01KT1605) (S.M.P., M.K.), IMI-JU ITCC-P4 (116064) (D.T.W.J., J.K., S.M.P., M.K.), and the Helmholtz International Graduate School for Cancer Research (S.B.).

Author information

Author notes

  1. Joyoti Dey

    Present address: Presage Biosciences, Seattle, WA, USA

  2. Lukas Chavez

    Present address: Department of Medicine, Division of Medical Genetics, University of California San Diego School of Medicine, La Jolla, CA, USA

  3. These authors contributed equally: Sebastian Brabetz, Sarah E. S. Leary, Susanne N. Gröbner.

  4. These authors jointly supervised this work: Stefan M. Pfister, Marcel Kool, James M. Olson.

Authors and Affiliations

  1. Hopp Children’s Cancer Center, NCT Heidelberg (KiTZ), Heidelberg, Germany

    Sebastian Brabetz, Susanne N. Gröbner, Norman L. Mack, Benjamin Schwalm, Gnana Prakash Balasubramanian, Lukas Chavez, David T. W. Jones, Stefan M. Pfister & Marcel Kool

  2. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Sebastian Brabetz, Susanne N. Gröbner, Huriye Şeker-Cin, Norman L. Mack, Benjamin Schwalm, Gnana Prakash Balasubramanian, Paul A. Northcott, Lukas Chavez, David T. W. Jones, Stefan M. Pfister & Marcel Kool

  3. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

    Sebastian Brabetz

  4. Seattle Children’s and University of Washington, Seattle, WA, USA

    Sarah E. S. Leary, Bonnie Cole & James M. Olson

  5. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Sarah E. S. Leary, Madison W. Nakamoto, Emily J. Girard, Andrew D. Strand, Karina L. Bloom, Fiona Pakiam, Kyle D. Pedro, Joyoti Dey, Stacey Hansen, Sally Ditzler & James M. Olson

  6. Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Volker Hovestadt, Norman L. Mack & Peter Lichter

  7. Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Volker Hovestadt

  8. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Volker Hovestadt

  9. CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Andrey Korshunov

  10. Department of Neuropathology, Heidelberg University, Heidelberg, Germany

    Andrey Korshunov

  11. Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Paul A. Northcott

  12. Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands

    Jan Koster

  13. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany

    Stefan M. Pfister

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Contributions

S.B., S.E.S.L., S.N.G., M.W.N., H.S.-C, E.J.G., B.C., A.D.S., K.L.B., N.L.M., F.P., B.S., A.K., K.D.P., J.D., S.H., and S.D. performed and/or coordinated the experimental work. S.B., S.E.S.L., S.N.G., M.W.N., H.S.-C., E.J.G, B.C., A.D.S., K.L.B., V.H., A.K., G.P.B., P.A.N., K.D.P., S.H., S.D., P.L., L.C., D.T.W.J., J.K., and M.K. performed data analysis and interpretation. S.B., S.E.S.L., S.N.G., S.M.P., M.K., and J.M.O. provided project leadership. S.B., S.E.S.L., S.N.G., S.M.P., M.K., and J.M.O. prepared the initial manuscript and figures. All authors contributed to the critical review of the manuscript.

Corresponding authors

Correspondence to Stefan M. Pfister, Marcel Kool or James M. Olson.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10

Reporting Summary

Supplementary Table 1

PDOX model information

Supplementary Table 2

Pathological characterization of PDOX models and matching human tumors

Supplementary Table 3

Overview about molecular data

Supplementary Table 4

Molecular alterations in PDOX models and matching human tumors

Supplementary Table 5

Genes with increased and decreased expression in PDOX compared to human tumors

Supplementary Table 6

Primers used for Sanger sequencing validations and for qRT–PCR

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Brabetz, S., Leary, S.E.S., Gröbner, S.N. et al. A biobank of patient-derived pediatric brain tumor models. Nat Med 24, 1752–1761 (2018). https://doi.org/10.1038/s41591-018-0207-3

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