Screening for Tumor Microtube-Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma Progression
Menée in vitro, in vivo et à l'aide d'outils d'analyse utilisant des algorithmes d'apprentissage automatique ainsi que d'une technique de criblage de médicaments dirigés contre les microtubes tumoraux (extensions membranaires permettant la communication entre deux cellules cancéreuses), cette étude met en évidence l'intérêt de modulateurs de protéine kinase C pour inhiber la progression d'un glioblastome
Glioblastomas are incurable primary brain tumors that depend on neural-like cellular processes, tumor microtubes (TMs), to invade the brain. TMs also interconnect single tumor cells to a communicating multicellular network that resists current therapies. Here, 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. Since TM-unconnected tumor cells exhibited increased sensitivity to cytotoxic therapy, the PKC activator TPPB was combined with radiotherapy, and long-term intravital 2-photon microscopy paired with spatially resolved multiomics revealed anti-TM and anti-tumor 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.
Cancer Discovery , résumé, 2025