Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma

Cancer Cell, vol. 40, pp. 639–655.e13

Abstract

Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas by spatially resolved transcriptomics, metabolomics, and proteomics. By deciphering regionally shared transcriptional programs across patients, we infer that glioblastoma is organized by spatial segregation of lineage states and adapts to inflammatory and/or metabolic stimuli, reminiscent of the reactive transformation in mature astrocytes. Integration of metabolic imaging and imaging mass cytometry uncovered locoregional tumor-host interdependence, resulting in spatially exclusive adaptive transcriptional programs. Inferring copy-number alterations emphasizes a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblastoma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments.

Authors 35

1. Vidhya Madapusi Ravi

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany; Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

   Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

   Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

   Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

   Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

2. Paulina Will

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

   Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

   Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

   Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

3. Jan Kueckelhaus Aachen Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA) Department of Neurosurgery

   University of Freiburg · University Medical Center Freiburg · RWTH Aachen University

   Affiliation as printed

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany; Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA), Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany

   Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

   Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

   Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA), Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany

   Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

4. Na Sun

   Helmholtz Munich

   Affiliation as printed

   Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany

5. Kevin Joseph

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany; Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

   Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

   Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

   Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

   Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

6. Henrike Salié

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center - University of Freiburg, Freiburg, Germany

   Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center - University of Freiburg, Freiburg, Germany

   Faculty of Medicine, University of Freiburg, Freiburg, Germany

7. Lea Vollmer

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

   Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

   Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

   Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

8. Ugnė Kuliešiūtė

   University of Freiburg · Vilnius University · University Medical Center Freiburg

   Affiliation as printed

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany; The Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

   The Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania

   Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

9. Jasmin von Ehr

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

   Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

   Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

   Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

10. Jasim Kada Benotmane

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

    Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

11. Nicolas Noel Neidert

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

    Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

12. Marie Follo

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Medicine I, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Medicine I, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

13. Florian Scherer

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Medicine I, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Medicine I, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

14. Jonathan M. Goeldner

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

    Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

15. Simon P. Behringer

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

    Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

16. Pamela Franco

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

17. Mohammed Khiat

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

    Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

18. Junyi Zhang

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

    Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

19. Ulrich Hofmann

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Neuroelectronic Systems, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Neuroelectronic Systems, Medical Center - University of Freiburg, Freiburg, Germany

20. Christian Fung

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

21. Franz Lennard Ricklefs

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany; Laboratory for Brain Tumor Biology, University Hospital Eppendorf, Hamburg, Germany

    Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany

    Laboratory for Brain Tumor Biology, University Hospital Eppendorf, Hamburg, Germany

22. Katrin Lamszus

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany; Laboratory for Brain Tumor Biology, University Hospital Eppendorf, Hamburg, Germany

    Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany

    Laboratory for Brain Tumor Biology, University Hospital Eppendorf, Hamburg, Germany

23. Melanie Boerries

    University of Freiburg · University Medical Center Freiburg · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Freiburg, Germany; Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany

    Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany

    Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Freiburg, Germany

24. Manching Ku

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

25. Jürgen Beck

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for NeuroModulation (NeuroModul), University of Freiburg, Freiburg, Germany; Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

    Center for NeuroModulation (NeuroModul), University of Freiburg, Freiburg, Germany

    Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

26. Roman Sankowski

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Neuropathology, Medical Center - University of Freiburg, Freiburg, German

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Institute of Neuropathology, Medical Center - University of Freiburg, Freiburg, German

27. Marius Schwabenland

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Neuropathology, Medical Center - University of Freiburg, Freiburg, German

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Institute of Neuropathology, Medical Center - University of Freiburg, Freiburg, German

28. Marco Prinz

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for NeuroModulation (NeuroModul), University of Freiburg, Freiburg, Germany; Institute of Neuropathology, Medical Center - University of Freiburg, Freiburg, German; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

    Center for NeuroModulation (NeuroModul), University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Institute of Neuropathology, Medical Center - University of Freiburg, Freiburg, German

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

29. Ulrich Schüller

    University Medical Center Hamburg-Eppendorf · Kinderkrebs-Zentrum Hamburg

    Affiliation as printed

    Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Research Institute Children's Cancer Center, Hamburg, Germany; Department of Pediatric Hematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    Department of Pediatric Hematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    Research Institute Children's Cancer Center, Hamburg, Germany

30. Saskia Killmer

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center - University of Freiburg, Freiburg, Germany

    Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

31. Bertram Bengsch

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center - University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

    Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

32. Axel Karl Walch

    Helmholtz Munich

    Affiliation as printed

    Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany

33. Daniel Delev Aachen Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA) Department of Neurosurgery

    RWTH Aachen University

    Affiliation as printed

    Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA), Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany; Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany

    Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany

    Neurosurgical Artificial Intelligence Laboratory Aachen (NAILA), Department of Neurosurgery, RWTH University of Aachen, Aachen, Germany

34. Oliver Schnell

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany; Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

    Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany

    Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany

35. Dieter Henrik Heiland corresponding

    University of Freiburg · University Medical Center Freiburg · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany; Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany. Electronic address: dieter.henrik.heiland@uniklinik-freiburg.de

    Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany

    Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Freiburg, Germany

    Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany

    Faculty of Medicine, University of Freiburg, Freiburg, Germany

    German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany

    Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany