A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1

Ling Hai, Dirk C. Hoffmann, Robin J. Wagener, Daniel D. Azorin, David Hausmann, Ruifan Xie, Magnus-Carsten Huppertz, Julien Hiblot, Philipp Sievers, Sophie Heuer, Jakob Ito, Gina Cebulla, Alexandros Kourtesakis, Leon D. Kaulen, Miriam Ratliff, Henriette Mandelbaum, Erik Jung, Ammar Jabali, Sandra Horschitz, Kati J. Ernst, Denise Reibold, Uwe Warnken, Varun Venkataramani, Rainer Will, Mario L. Suvà, Christel Herold-Mende, Felix Sahm, Frank Winkler, Matthias Schlesner, Wolfgang Wick and Tobias Kessler ()
Additional contact information
Ling Hai: German Cancer Research Center (DKFZ)
Dirk C. Hoffmann: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Robin J. Wagener: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Daniel D. Azorin: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
David Hausmann: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Ruifan Xie: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Magnus-Carsten Huppertz: Max Planck Institute for Medical Research
Julien Hiblot: Max Planck Institute for Medical Research
Philipp Sievers: Institute of Pathology
Sophie Heuer: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Jakob Ito: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Gina Cebulla: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Alexandros Kourtesakis: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Leon D. Kaulen: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Miriam Ratliff: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Henriette Mandelbaum: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Erik Jung: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Ammar Jabali: Central Institute of Mental Health, Heidelberg University
Sandra Horschitz: Central Institute of Mental Health, Heidelberg University
Kati J. Ernst: Pediatric Glioma Research Group, DKTK, DKFZ
Denise Reibold: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Uwe Warnken: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Varun Venkataramani: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Rainer Will: Genomics and Proteomics Core Facility, DKTK, DKFZ
Mario L. Suvà: Broad Institute of Harvard and MIT
Christel Herold-Mende: Heidelberg University Hospital
Felix Sahm: Institute of Pathology
Frank Winkler: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Matthias Schlesner: German Cancer Research Center (DKFZ)
Wolfgang Wick: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Tobias Kessler: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)

Nature Communications, 2024, vol. 15, issue 1, 1-29

Abstract: Abstract Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging and the impact on patient survival unresolved. Here, we establish a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells using a dye uptake methodology, and validate it with recording of cellular calcium epochs and clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, TM-network connectivity correlates with the mesenchymal subtype and dismal patient survival. CHI3L1 gene expression serves as a robust molecular marker of connectivity and functionally influences TM networks. The connectivity signature allows insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.

Date: 2024
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Citations: View citations in EconPapers (2)

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DOI: 10.1038/s41467-024-45067-8

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