Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade

• Verfasst von: Phillips, Emma [VerfasserIn]
• Verfasst von: van Enk, Sizèd [VerfasserIn]
• Verfasst von: Kildgaard, Sara [VerfasserIn]
• Verfasst von: Schlue, Silja [VerfasserIn]
• Verfasst von: Göttmann, Mona [VerfasserIn]
• Verfasst von: Jennings, Victoria [VerfasserIn]
• Verfasst von: Bethke, Frederic [VerfasserIn]
• Verfasst von: Müller, Gabriele [VerfasserIn]
• Verfasst von: Herold-Mende, Christel [VerfasserIn]
• Verfasst von: Pastor-Flores, Daniel [VerfasserIn]
• Verfasst von: Schneider, Martin [VerfasserIn]
• Verfasst von: Helm, Dominic [VerfasserIn]
• Verfasst von: Ostenfeld Larsen, Thomas [VerfasserIn]
• Verfasst von: Goidts, Violaine [VerfasserIn]
• Titel: Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade
• Verf.angabe: Emma Phillips, Sizèd van Enk, Sara Kildgaard, Silja Schlue, Mona Göttmann, Victoria Jennings, Frederic Bethke, Gabriele Müller, Christel Herold-Mende, Daniel Pastor-Flores, Martin Schneider, Dominic Helm, Thomas Ostenfeld Larsen, Violaine Goidts
• E-Jahr: 2025
• Jahr: 27 October 2024
• Umfang: 23 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 29.04.2025
• Titel Quelle: Enthalten in: Molecular oncology
• Ort Quelle: Hoboken, NJ : John Wiley & Sons, Inc., 2007
• Jahr Quelle: 2025
• Band/Heft Quelle: 19(2025), 3, Seite 785-807
• ISSN Quelle: 1878-0261
• DOI: doi:10.1002/1878-0261.13756
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Animals
• Sach-SW: autophagy
• Sach-SW: Autophagy
• Sach-SW: Brain Neoplasms
• Sach-SW: cancer
• Sach-SW: Cell Line, Tumor
• Sach-SW: compound screen
• Sach-SW: glioblastoma
• Sach-SW: Glioblastoma
• Sach-SW: Humans
• Sach-SW: Mice
• Sach-SW: Neoplastic Stem Cells
• Sach-SW: proteostasis
• Sach-SW: Proteotoxic Stress
• Sach-SW: stem cells
• Sach-SW: unfolded protein response
• Sach-SW: Unfolded Protein Response
• Sach-SW: Xenograft Model Antitumor Assays
• K10plus-PPN: 1923883194

Abstract

Glioblastoma is a highly aggressive brain tumor for which there is no cure. The dire prognosis of this disease is largely attributable to a high level of heterogeneity, including the presence of a subpopulation of tumor-initiating glioblastoma stem-like cells (GSCs), which are refractory to chemo- and radiotherapy. Here, in an unbiased marine-derived fungal extract screen, together with bioguided dereplication based on high-resolution mass spectrometry, we identified malformin C to preferentially induce cell death in patient-derived GSCs and explore the potential of this cyclic peptide as a therapeutic agent for glioblastoma. Malformin C significantly reduced tumor growth in an in vivo xenograft model of glioblastoma. Using transcriptomics and chemoproteomics, we found that malformin C binds to many proteins, leading to their aggregation, and rapidly induces the unfolded protein response, including autophagy, in GSCs. Crucially, chemical inhibition of translation using cycloheximide rescued malformin C-induced cell death in GSCs, demonstrating that the proteotoxic effect of the compound is necessary for its cytotoxicity. At the same time, malformin C appears to accumulate in lysosomes, disrupting autophagic flux, and driving cells to death. Supporting this, malformin C synergizes with chloroquine, an inhibitor of autophagy. Strikingly, we observed that autophagic flux is differentially regulated in GSCs compared with normal astrocytes. The sensitivity of GSCs to malformin C highlights the relevance of proteostasis and autophagy as a therapeutic vulnerability in glioblastoma.