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@ARTICLE{Phillips:294336,
      author       = {E. Phillips$^*$ and S. van Enk$^*$ and S. Kildgaard and S.
                      Schlue$^*$ and M. Göttmann$^*$ and L. V. Jennings$^*$ and
                      F. Bethke$^*$ and G. Müller$^*$ and C. Herold-Mende and D.
                      Pastor-Flores$^*$ and M. Schneider$^*$ and D. Helm$^*$ and
                      T. Ostenfeld Larsen and V. Goidts$^*$},
      title        = {{M}alformin {C} preferentially kills glioblastoma stem-like
                      cells via concerted induction of proteotoxic stress and
                      autophagic flux blockade.},
      journal      = {Molecular oncology},
      volume       = {19},
      number       = {3},
      issn         = {1574-7891},
      address      = {Hoboken, NJ},
      publisher    = {John Wiley $\&$ Sons, Inc.},
      reportid     = {DKFZ-2024-02169},
      pages        = {785-807},
      year         = {2025},
      note         = {#EA:B067#LA:B067# / 2025 Mar;19(3):785-807},
      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.},
      keywords     = {autophagy (Other) / cancer (Other) / compound screen
                      (Other) / glioblastoma (Other) / proteostasis (Other) / stem
                      cells (Other) / unfolded protein response (Other)},
      cin          = {B067 / A160 / W120},
      ddc          = {610},
      cid          = {I:(DE-He78)B067-20160331 / I:(DE-He78)A160-20160331 /
                      I:(DE-He78)W120-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39462997},
      doi          = {10.1002/1878-0261.13756},
      url          = {https://inrepo02.dkfz.de/record/294336},
}