Research findings related to UNITE work package A01/A03/A06/A07/ B04/D01
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.
Hai L*, Hoffmann DC*, Wagener RJ, Azorin DD*, Hausmann D*, Xie R, Huppertz MC, Hiblot J, Sievers P, Heuer S*, Ito J, Cebulla G, Kourtesakis A, Kaulen LD, Ratliff M*, Mandelbaum H, Jung E, Jabali A, Horschitz S, Ernst KJ, Reibold D, Warnken U, Venkataramani V*, Will R, Suvà ML, Herold-Mende C*, Sahm F*, Winkler F*, Schlesner M*, Wick W*, Kessler T.* A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1. Nat Commun. 2024 Feb 6;15(1):968. doi: 10.1038/s41467-024-45067-8. PMID: 38320988; PMCID: PMC10847113. * UNITE Principal Investigators and Fellows
