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Screening for tumor microtube-targeting drugs identifies PKC modulators as multipotent inhibitors of glioblastoma progression

Glioblastomas are incurable primary brain tumors that depend on neural-like cellular processes, tumor microtubes (TM), to invade the brain. TMs also interconnect single tumor cells to a communicating multicellular network that resists current therapies. In this study, we developed a combined, compre...

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Main Authors: Domínguez Azorín, Daniel (Author) , Hoffmann, Dirk C. (Author) , Hebach, Nils R. (Author) , Jung, Erik (Author) , Hausmann, David (Author) , Ratliff, Miriam (Author) , Hai, Ling (Author) , Horschitz, Sandra (Author) , Jabali, Ammar (Author) , Osswald, Matthias (Author) , Karreman, Matthia A. (Author) , Kessler, Tobias (Author) , Wendler, Susann (Author) , Mayer, Chanté D. (Author) , Löb, Cathrin (Author) , Lehnert, Pascal (Author) , Cebulla, Gina (Author) , Reibold, Denise (Author) , Khajuria, Rajiv K. (Author) , Bordignon, Pino (Author) , Moor, Andreas E. (Author) , Holland-Letz, Tim (Author) , Reckless, Jill (Author) , Ramsden, Nigel (Author) , Grainger, David (Author) , Kreshuk, Anna (Author) , Koch, Philipp (Author) , Wick, Wolfgang (Author) , Heuer, Sophie (Author) , Winkler, Frank (Author)
Format: Article (Journal)
Language:English
Published: 1 February 2026
In: Cancer discovery
Year: 2026, Volume: 16, Issue: 2, Pages: 367-390
ISSN:2159-8290
DOI:10.1158/2159-8290.CD-24-0414
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/2159-8290.CD-24-0414
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Author Notes:Daniel D. Azorín, Dirk C. Hoffmann, Nils R. Hebach, Erik Jung, David Hausmann, Miriam Ratliff, Ling Hai, Sandra Horschitz, Ammar Jabali, Matthias Osswald, Matthia A. Karreman, Tobias Kessler, Susann Wendler, Chanté D. Mayer, Cathrin Löb, Pascal Lehnert, Gina Cebulla, Denise Reibold, Rajiv K. Khajuria, Pino Bordignon, Andreas E. Moor, Tim Holland-Letz, Jill Reckless, Nigel Ramsden, David Grainger, Anna Kreshuk, Philipp Koch, Wolfgang Wick, Sophie Heuer, and Frank Winkler
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Summary:Glioblastomas are incurable primary brain tumors that depend on neural-like cellular processes, tumor microtubes (TM), to invade the brain. TMs also interconnect single tumor cells to a communicating multicellular network that resists current therapies. In this study, we developed a combined, comprehensive in vitro/in vivo anti-TM drug screening approach, including machine learning–based analysis tools. Two protein kinase C (PKC) modulators robustly inhibited TM formation and pacemaker tumor cell–driven, TM-mediated glioblastoma cell network communication. As TM-unconnected tumor cells exhibited increased sensitivity to cytotoxic therapy, the PKC activator TPPB was combined with radiotherapy, and long-term intravital two-photon microscopy paired with spatially resolved multiomics revealed anti-TM and antitumor effects. TPPB treatment also decreased the expression of tweety family member 1 (TTYH1), a key driver of invasive TMs. Our study establishes a novel screening pipeline for anti-TM drug development, identifies a TM master regulator pathway, and supports the approach of TM targeting for efficient brain tumor therapies.
Item Description:Gesehen am 09.03.2026
Physical Description:Online Resource
ISSN:2159-8290
DOI:10.1158/2159-8290.CD-24-0414

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