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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\u2013based analysis tools. Two protein kinase C (PKC) modulators robustly inhibited TM formation and pacemaker tumor cell\u2013driven, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Cancers can hijack neural properties to grow, disseminate, and to resist therapies, but effective drug development pipelines against these features are missing. Here, we establish a compound screening approach that allowed the identification of PKC modulators that target cancer cell\u2013intrinsic neurodevelopmental mechanisms, suggesting a new class of neuroscience-instructed cancer therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-0414","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T12:15:37Z","timestamp":1760012137000},"page":"367-390","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Screening for Tumor Microtube\u2013Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma Progression"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0002-4307","authenticated-orcid":false,"given":"Daniel D.","family":"Azor\u00edn","sequence":"first","affiliation":[{"name":"1Heidelberg University Medical Faculty, Neurology Clinic, and National Center for Tumor Diseases, Heidelberg, Germany."},{"name":"2Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany."},{"name":"3Faculty of Biosciences, Heidelberg University, Heidelberg, Germany."},{"name":"4Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1370-1933","authenticated-orcid":false,"given":"Dirk C.","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"1Heidelberg University Medical Faculty, Neurology Clinic, and National Center for Tumor Diseases, Heidelberg, Germany."},{"name":"2Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany."},{"name":"3Faculty of Biosciences, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1921-3244","authenticated-orcid":false,"given":"Nils R.","family":"Hebach","sequence":"additional","affiliation":[{"name":"1Heidelberg University Medical Faculty, Neurology Clinic, and National Center for Tumor Diseases, Heidelberg, Germany."},{"name":"2Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5016-8202","authenticated-orcid":false,"given":"Erik","family":"Jung","sequence":"additional","affiliation":[{"name":"1Heidelberg University Medical Faculty, Neurology Clinic, and National Center for Tumor Diseases, Heidelberg, Germany."},{"name":"2Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, 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