Malformin C preferentially kills glioblastoma stem‐like cells via concerted induction of proteotoxic stress and autophagic flux blockade
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‐ a...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13756 |
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| author | Emma Phillips Sizèd vanEnk 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 |
| author_facet | Emma Phillips Sizèd vanEnk 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 |
| author_sort | Emma Phillips |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0ec555fe0b3a42eeb8581e43b438aae2 |
| institution | DOAJ |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-0ec555fe0b3a42eeb8581e43b438aae22025-08-20T02:59:42ZengWileyMolecular Oncology1574-78911878-02612025-03-0119378580710.1002/1878-0261.13756Malformin C preferentially kills glioblastoma stem‐like cells via concerted induction of proteotoxic stress and autophagic flux blockadeEmma Phillips0Sizèd vanEnk1Sara Kildgaard2Silja Schlue3Mona Göttmann4Victoria Jennings5Frederic Bethke6Gabriele Müller7Christel Herold‐Mende8Daniel Pastor‐Flores9Martin Schneider10Dominic Helm11Thomas Ostenfeld Larsen12Violaine Goidts13Junior Research Group “Brain Tumor Translational Targets” German Cancer Research Center (DKFZ) Heidelberg GermanyJunior Research Group “Brain Tumor Translational Targets” German Cancer Research Center (DKFZ) Heidelberg GermanyDepartment of Biotechnology and Biomedicine, Section for Microbial and Chemical Ecology, Natural Product Discovery Technical University of Denmark Copenhagen DenmarkJunior Research Group “Brain Tumor Translational Targets” German Cancer Research Center (DKFZ) Heidelberg GermanyJunior Research Group “Brain Tumor Translational Targets” German Cancer Research Center (DKFZ) Heidelberg GermanyJunior Research Group “Brain Tumor Translational Targets” German Cancer Research Center (DKFZ) Heidelberg GermanyJunior Research Group “Brain Tumor Translational Targets” German Cancer Research Center (DKFZ) Heidelberg GermanyJunior Research Group “Brain Tumor Translational Targets” German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Neurosurgical Research, Department of Neurosurgery University Hospital Heidelberg GermanyDivision of Redox Regulation German Cancer Research Center (DKFZ) Heidelberg GermanyProteomics Core Facility German Cancer Research Center (DKFZ) Heidelberg GermanyProteomics Core Facility German Cancer Research Center (DKFZ) Heidelberg GermanyDepartment of Biotechnology and Biomedicine, Section for Microbial and Chemical Ecology, Natural Product Discovery Technical University of Denmark Copenhagen DenmarkJunior Research Group “Brain Tumor Translational Targets” German Cancer Research Center (DKFZ) Heidelberg GermanyGlioblastoma 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.https://doi.org/10.1002/1878-0261.13756autophagycancercompound screenglioblastomaproteostasisstem cells |
| spellingShingle | Emma Phillips Sizèd vanEnk 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 Malformin C preferentially kills glioblastoma stem‐like cells via concerted induction of proteotoxic stress and autophagic flux blockade Molecular Oncology autophagy cancer compound screen glioblastoma proteostasis stem cells |
| title | Malformin C preferentially kills glioblastoma stem‐like cells via concerted induction of proteotoxic stress and autophagic flux blockade |
| title_full | Malformin C preferentially kills glioblastoma stem‐like cells via concerted induction of proteotoxic stress and autophagic flux blockade |
| title_fullStr | Malformin C preferentially kills glioblastoma stem‐like cells via concerted induction of proteotoxic stress and autophagic flux blockade |
| title_full_unstemmed | Malformin C preferentially kills glioblastoma stem‐like cells via concerted induction of proteotoxic stress and autophagic flux blockade |
| title_short | Malformin C preferentially kills glioblastoma stem‐like cells via concerted induction of proteotoxic stress and autophagic flux blockade |
| title_sort | malformin c preferentially kills glioblastoma stem like cells via concerted induction of proteotoxic stress and autophagic flux blockade |
| topic | autophagy cancer compound screen glioblastoma proteostasis stem cells |
| url | https://doi.org/10.1002/1878-0261.13756 |
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