Glioblastomas are aggressive brain tumors for which effective therapy is still lacking, resulting in dismal survival rates. These tumors display significant phenotypic plasticity, harboring diverse cell populations ranging from tumor core cells to dispersed, highly invasive cells. Neuron navigator 3 (NAV3), a microtubule-associated protein affecting microtubule growth and dynamics, is downregulated in various cancers, including glioblastoma, and has thus been considered a tumor suppressor. In this study, we challenge this designation and unveil distinct expression patterns of NAV3 across different invasion phenotypes. Using glioblastoma cell lines and patient-derived glioma stem-like cell cultures, we disclose an upregulation of NAV3 in invading glioblastoma cells, contrasting with its lower expression in cells residing in tumor spheroid cores. Furthermore, we establish an association between low and high NAV3 expression and the amoeboid and mesenchymal invasive phenotype, respectively, and demonstrate that overexpression of NAV3 directly stimulates glioblastoma invasive behavior in both 2D and 3D environments. Consistently, we observed increased NAV3 expression in cells migrating along blood vessels in mouse xenografts. Overall, our results shed light on the role of NAV3 in glioblastoma invasion, providing insights into this lethal aspect of glioblastoma behavior.

• Klíčová slova
• NAV3, amoeboid, glioblastoma, invasion, mesenchymal,
• MeSH
• fenotyp * MeSH
• glioblastom * patologie   genetika   metabolismus   MeSH
• invazivní růst nádoru * genetika   MeSH
• lidé MeSH
• membránové proteiny MeSH
• mikrotubuly metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory mozku * patologie   genetika   metabolismus   MeSH
• pohyb buněk genetika   fyziologie   MeSH
• proteiny nervové tkáně metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové proteiny MeSH
• NAV3 protein, human MeSH Prohlížeč
• proteiny nervové tkáně MeSH

Gliomagenesis induces profound changes in the composition of the extracellular matrix (ECM) of the brain. In this study, we identified a cellular population responsible for the increased deposition of collagen I and fibronectin in glioblastoma. Elevated levels of the fibrillar proteins collagen I and fibronectin were associated with the expression of fibroblast activation protein (FAP), which is predominantly found in pericyte-like cells in glioblastoma. FAP+ pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in the GBM microenvironment. Using mass spectrometry, we demonstrated that 3D matrices produced by FAP+ pericyte-like cells are rich in collagen I and fibronectin and contain several basement membrane proteins. This expression pattern differed markedly from glioma cells. Finally, we have shown that ECM produced by FAP+ pericyte-like cells enhances the migration of glioma cells including glioma stem-like cells, promotes their adhesion, and activates focal adhesion kinase (FAK) signaling. Taken together, our findings establish FAP+ pericyte-like cells as crucial producers of a complex ECM rich in collagen I and fibronectin, facilitating the dissemination of glioma cells through FAK activation.

• Klíčová slova
• collagen type I, extracellular matrix proteins, fibronectin, glioblastoma, pericytes, proteomics,
• MeSH
• endopeptidasy MeSH
• extracelulární matrix * metabolismus   patologie   MeSH
• fibronektiny * metabolismus   MeSH
• glioblastom patologie   metabolismus   MeSH
• gliom * patologie   metabolismus   MeSH
• kolagen typu I metabolismus   MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí fyziologie   MeSH
• nádory mozku * patologie   metabolismus   MeSH
• pericyty * metabolismus   patologie   MeSH
• pohyb buněk fyziologie   MeSH
• serinové endopeptidasy metabolismus   MeSH
• želatinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endopeptidasy MeSH
• fibroblast activation protein alpha MeSH Prohlížeč
• fibronektiny * MeSH
• kolagen typu I MeSH
• membránové proteiny MeSH
• serinové endopeptidasy MeSH
• želatinasy MeSH

Glioblastoma multiforme (GBM) represents approximately 60% of all brain tumors in adults. This malignancy shows a high biological and genetic heterogeneity associated with exceptional aggressiveness, leading to a poor survival of patients. This review provides a summary of the basic biology of GBM cells with emphasis on cell cycle and cytoskeletal apparatus of these cells, in particular microtubules. Their involvement in the important oncosuppressive process called mitotic catastrophe will next be discussed along with select examples of microtubule-targeting agents, which are currently explored in this respect such as benzimidazole carbamate compounds. Select microtubule-targeting agents, in particular benzimidazole carbamates, induce G2/M cell cycle arrest and mitotic catastrophe in tumor cells including GBM, resulting in phenotypically variable cell fates such as mitotic death or mitotic slippage with subsequent cell demise or permanent arrest leading to senescence. Their effect is coupled with low toxicity in normal cells and not developed chemoresistance. Given the lack of efficient cytostatics or modern molecular target-specific compounds in the treatment of GBM, drugs inducing mitotic catastrophe might offer a new, efficient alternative to the existing clinical management of this at present incurable malignancy.

• Klíčová slova
• benzimidazole carbamates, cell death, glioblastoma multiforme, microtubule-targeting agents, mitotic catastrophe,
• MeSH
• glioblastom * metabolismus   mortalita   terapie   MeSH
• kontrolní body fáze G2 buněčného cyklu * MeSH
• kontrolní body M fáze buněčného cyklu * MeSH
• lidé MeSH
• mitóza * MeSH
• nádory mozku * metabolismus   mortalita   patologie   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH