%0 Journal Article
%A Phillips, Emma
%A van Enk, Sizèd
%A Kildgaard, Sara
%A Schlue, Silja
%A Göttmann, Mona
%A Jennings, Lauren Victoria
%A Bethke, Frederic
%A Müller, Gabriele
%A Herold-Mende, Christel
%A Pastor-Flores, Daniel
%A Schneider, Martin
%A Helm, Dominic
%A Ostenfeld Larsen, Thomas
%A Goidts, Violaine
%T Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade.
%J Molecular oncology
%V 19
%N 3
%@ 1574-7891
%C Hoboken, NJ
%I John Wiley & Sons, Inc.
%M DKFZ-2024-02169
%P 785-807
%D 2025
%Z #EA:B067#LA:B067# / 2025 Mar;19(3):785-807
%X 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.
%K autophagy (Other)
%K cancer (Other)
%K compound screen (Other)
%K glioblastoma (Other)
%K proteostasis (Other)
%K stem cells (Other)
%K unfolded protein response (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39462997
%R 10.1002/1878-0261.13756
%U https://inrepo02.dkfz.de/record/294336