Thomas K Albert1, Marta Interlandi1,2, Martin Sill3,4, Monika Graf1, Natalia Moreno1, Kerstin Menck5, Astrid Rohlmann5,6, Viktoria Melcher1, Sonja Korbanka1, Gerd Meyer Zu Hörste7, Tobias Lautwein8, Michael C Frühwald9, Christian F Krebs10, Dörthe Holdhof11,12, Melanie Schoof11,12, Annalen Bleckmann5, Markus Missler6, Martin Dugas2, Ulrich Schüller11,12,13, Natalie Jäger3, Stefan M Pfister3,4,14,15, Kornelius Kerl1. 1. Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany. 2. Institute of Medical Informatics, Westphalian-Wilhelms-University (WWU) Münster, Münster, Germany. 3. Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany. 4. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 5. Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster (UKM), Münster, Germany. 6. Department of Anatomy and Molecular Neurobiology, WWU Münster, Münster, Germany. 7. Department of Neurology, UKM, Münster, Germany. 8. Biological and Medical Research Center, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 9. Swabian Children's Cancer Center, Children's Hospital Augsburg, Augsburg, Germany. 10. Center for Internal Medicine, III. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 11. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 12. Research Institute Children's Cancer Center, Hamburg, Germany. 13. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 14. German Cancer Consortium (DKTK) Heidelberg, Heidelberg, Germany. 15. Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.
Abstract
BACKGROUND: Medulloblastoma (MB) is a malignant brain tumor in childhood. It comprises 4 subgroups with different clinical behaviors. The aim of this study was to characterize the transcriptomic landscape of MB, both at the level of individual tumors as well as in large patient cohorts. METHODS: We used a combination of single-cell transcriptomics, cell culture models and biophysical methods such as nanoparticle tracking analysis and electron microscopy to investigate intercellular communication in the MB tumor niche. RESULTS: Tumor cells of the sonic hedgehog (SHH)-MB subgroup show a differentiation blockade. These cells undergo extensive metabolic reprogramming. The gene expression profiles of individual tumor cells show a partial convergence with those of tumor-associated glial and immune cells. One possible cause is the transfer of extracellular vesicles (EVs) between cells in the tumor niche. We were able to detect EVs in co-culture models of MB tumor cells and oligodendrocytes. We also identified a gene expression signature, EVS, which shows overlap with the proteome profile of large oncosomes from prostate cancer cells. This signature is also present in MB patient samples. A high EVS expression is one common characteristic of tumors that occur in high-risk patients from different MB subgroups or subtypes. CONCLUSIONS: With EVS, our study uncovered a novel gene expression signature that has a high prognostic significance across MB subgroups.
BACKGROUND:Medulloblastoma (MB) is a malignant brain tumor in childhood. It comprises 4 subgroups with different clinical behaviors. The aim of this study was to characterize the transcriptomic landscape of MB, both at the level of individual tumors as well as in large patient cohorts. METHODS: We used a combination of single-cell transcriptomics, cell culture models and biophysical methods such as nanoparticle tracking analysis and electron microscopy to investigate intercellular communication in the MB tumor niche. RESULTS:Tumor cells of the sonic hedgehog (SHH)-MB subgroup show a differentiation blockade. These cells undergo extensive metabolic reprogramming. The gene expression profiles of individual tumor cells show a partial convergence with those of tumor-associated glial and immune cells. One possible cause is the transfer of extracellular vesicles (EVs) between cells in the tumor niche. We were able to detect EVs in co-culture models of MB tumor cells and oligodendrocytes. We also identified a gene expression signature, EVS, which shows overlap with the proteome profile of large oncosomes from prostate cancer cells. This signature is also present in MB patient samples. A high EVS expression is one common characteristic of tumors that occur in high-risk patients from different MB subgroups or subtypes. CONCLUSIONS: With EVS, our study uncovered a novel gene expression signature that has a high prognostic significance across MB subgroups.
Authors: Viktoria Melcher; Monika Graf; Marta Interlandi; Natalia Moreno; Flavia W de Faria; Su Na Kim; Dennis Kastrati; Sonja Korbanka; Amelie Alfert; Joachim Gerß; Gerd Meyer Zu Hörste; Wolfgang Hartmann; Michael C Frühwald; Martin Dugas; Ulrich Schüller; Martin Hasselblatt; Thomas K Albert; Kornelius Kerl Journal: Acta Neuropathol Date: 2019-12-17 Impact factor: 17.088
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