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

2024; Nature Portfolio; Volume: 15; Issue: 1 Linguagem: Inglês

10.1038/s41467-024-45067-8

2041-1723

Ling Hai, Dirk C. Hoffmann, Robin J. Wagener, Daniel Domínguez Azorín, 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 Ernst, Denise Reibold, Uwe Warnken, Varun Venkataramani, Rainer Will, Mario L. Suvà, Christel Herold‐Mende, Felix Sahm, Frank Winkler, Matthias Schlesner, Wolfgang Wick, Tobias Keßler,

Mathematical Biology Tumor Growth

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.