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Spatially Resolved Multi-Omics Deciphers Bidirectional Tumor-Host Interdependence in Glioblastoma

2021; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.3865275

1556-5068

Vidhya M. Ravi, Paulina Will, Jan Kueckelhaus, Na Sun, Kevin Joseph, Henrike Salié, Lea Vollmer, Ugnė Kuliešiūtė, Jasmin von Ehr, Jasim Kada Benotmane, Nicolas Neidert, Marie Follo, Florian Scherer, Jonathan M. Goeldner, Simon P. Behringer, Pamela Franco, Mohammed Khiat, Junyi Zhang, Ulrich Hofmann, Christian Fung, Franz Ricklefs, Katrin Lamszus, Melanie Boerries, Manching Ku, Jürgen Beck, Roman Sankowski, Marius Schwabenland, Marco Prinz, Ulrich Schüller, Saskia Killmer, Bertram Bengsch, Axel Walch, Daniel Delev, Oliver Schnell, Dieter Henrik Heiland,

Single-cell and spatial transcriptomics

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 Kröner-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 für Bildung und Forschung) (project number: FMT 13GW0230A), US was supported by the Fördergemeinschaft 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).