TY  - JOUR
AU  - Phillips, Emma
AU  - van Enk, Sizèd
AU  - Kildgaard, Sara
AU  - Schlue, Silja
AU  - Göttmann, Mona
AU  - Jennings, Lauren Victoria
AU  - Bethke, Frederic
AU  - Müller, Gabriele
AU  - Herold-Mende, Christel
AU  - Pastor-Flores, Daniel
AU  - Schneider, Martin
AU  - Helm, Dominic
AU  - Ostenfeld Larsen, Thomas
AU  - Goidts, Violaine
TI  - Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade.
JO  - Molecular oncology
VL  - 19
IS  - 3
SN  - 1574-7891
CY  - Hoboken, NJ
PB  - John Wiley & Sons, Inc.
M1  - DKFZ-2024-02169
SP  - 785-807
PY  - 2025
N1  - #EA:B067#LA:B067# / 2025 Mar;19(3):785-807
AB  - 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.
KW  - autophagy (Other)
KW  - cancer (Other)
KW  - compound screen (Other)
KW  - glioblastoma (Other)
KW  - proteostasis (Other)
KW  - stem cells (Other)
KW  - unfolded protein response (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39462997
DO  - DOI:10.1002/1878-0261.13756
UR  - https://inrepo02.dkfz.de/record/294336
ER  -