Cell Reports (Jul 2020)
A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
- Patrik Johansson,
- Cecilia Krona,
- Soumi Kundu,
- Milena Doroszko,
- Sathishkumar Baskaran,
- Linnéa Schmidt,
- Claire Vinel,
- Elin Almstedt,
- Ramy Elgendy,
- Ludmila Elfineh,
- Caroline Gallant,
- Sara Lundsten,
- Fernando J. Ferrer Gago,
- Aleksi Hakkarainen,
- Petra Sipilä,
- Maria Häggblad,
- Ulf Martens,
- Bo Lundgren,
- Melanie M. Frigault,
- David P. Lane,
- Fredrik J. Swartling,
- Lene Uhrbom,
- Marika Nestor,
- Silvia Marino,
- Sven Nelander
Affiliations
- Patrik Johansson
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Cecilia Krona
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Soumi Kundu
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Milena Doroszko
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Sathishkumar Baskaran
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Linnéa Schmidt
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Claire Vinel
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
- Elin Almstedt
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Ramy Elgendy
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Ludmila Elfineh
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Caroline Gallant
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Sara Lundsten
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Fernando J. Ferrer Gago
- Laboratory, Agency for Science, Technology and Research (A∗STAR), Singapore 138648, Singapore
- Aleksi Hakkarainen
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, 20500 Turku, Finland
- Petra Sipilä
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, 20500 Turku, Finland
- Maria Häggblad
- Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 104 05 Stockholm, Sweden
- Ulf Martens
- Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 104 05 Stockholm, Sweden
- Bo Lundgren
- Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, 104 05 Stockholm, Sweden
- Melanie M. Frigault
- AstraZeneca Oncology, Waltham, MA 02451, USA
- David P. Lane
- Laboratory, Agency for Science, Technology and Research (A∗STAR), Singapore 138648, Singapore; Dept of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institutet, 17177 Stockholm, Sweden
- Fredrik J. Swartling
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Lene Uhrbom
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Marika Nestor
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden
- Silvia Marino
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
- Sven Nelander
- Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden; Corresponding author
- Journal volume & issue
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Vol. 32,
no. 2
p. 107897
Abstract
Summary: Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells. We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.
