Simon P Behringer, Vidhya M Ravi, Oliver Schnell, Jasim Kada Benotmane, Henrike Salié, Marie Follo, Daniel Delev, Marius Schwabenland, Ulrich G. Hofmann, Melanie Boerries, Jonathan M Goeldner, Mohammed Khiat, Christian Fung, Manching Ku, Axel Walch, Jürgen Beck, Dieter Henrik Heiland, Ugne Kuliesiute, Florian Scherer, Ulrich Schüller, Paulina Will, Lea Vollmer, Na Sun, Pamela Franco, Roman Sankowski, Jasmin von Ehr, Kevin Joseph, Marco Prinz, Katrin Lamszus, Franz Ricklefs, Junyi Zhang, Jan Kueckelhaus, Saskia Killmer, Nicolas Neidert, and Bertram Bengsch
Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of the dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas in-depth by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering regional shared transcriptional programs across patients, we infer that glioblastomas are organized by spatial segregation of lineage states and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Integration of metabolic imaging and image 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. Funding: DHH is funded by the Else Kroner-Fresenius Foundation. The work is part of the MEPHISTO project (PI: DHH and DD), funded by BMBF (iGerman Ministry of Education and Research) (project number: 031L0260B). The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supports the work of AW (project number: SFB 824 C04). VR, KJ and UGH funded by BMBF (Bundes Ministerium fur Bildung und Forschung) (project number: FMT 13GW0230A), US was supported by the Fordergemeinschaft Kinderkrebszentrum Hamburg. We thank Dietmar Pfeifer for here helpful advice. We thank Biorender.com. We thank Stella Maria Carro for her support and the provision of her laboratory facilities and equipment. Declaration of Interest: No potential conflicts of interest were disclosed by the authors. Ethical Approval: The local ethics committee of the University of Freiburg approved the data evaluation, imaging procedures and experimental design (protocol 100020/09 and 472/15_160880).