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000294336 1001_ $$0P:(DE-He78)830be4979a39935ac6272eaebad5982a$$aPhillips, Emma$$b0$$eFirst author$$udkfz
000294336 245__ $$aMalformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade.
000294336 260__ $$aHoboken, NJ$$bJohn Wiley & Sons, Inc.$$c2025
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000294336 500__ $$a#EA:B067#LA:B067# / 2025 Mar;19(3):785-807
000294336 520__ $$aGlioblastoma is a highly aggressive brain tumor for which there is no cure. The dire prognosis of this disease is largely attributable to a high level of heterogeneity, including the presence of a subpopulation of tumor-initiating glioblastoma stem-like cells (GSCs), which are refractory to chemo- and radiotherapy. Here, in an unbiased marine-derived fungal extract screen, together with bioguided dereplication based on high-resolution mass spectrometry, we identified malformin C to preferentially induce cell death in patient-derived GSCs and explore the potential of this cyclic peptide as a therapeutic agent for glioblastoma. Malformin C significantly reduced tumor growth in an in vivo xenograft model of glioblastoma. Using transcriptomics and chemoproteomics, we found that malformin C binds to many proteins, leading to their aggregation, and rapidly induces the unfolded protein response, including autophagy, in GSCs. Crucially, chemical inhibition of translation using cycloheximide rescued malformin C-induced cell death in GSCs, demonstrating that the proteotoxic effect of the compound is necessary for its cytotoxicity. At the same time, malformin C appears to accumulate in lysosomes, disrupting autophagic flux, and driving cells to death. Supporting this, malformin C synergizes with chloroquine, an inhibitor of autophagy. Strikingly, we observed that autophagic flux is differentially regulated in GSCs compared with normal astrocytes. The sensitivity of GSCs to malformin C highlights the relevance of proteostasis and autophagy as a therapeutic vulnerability in glioblastoma.
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000294336 650_7 $$2Other$$aautophagy
000294336 650_7 $$2Other$$acancer
000294336 650_7 $$2Other$$acompound screen
000294336 650_7 $$2Other$$aglioblastoma
000294336 650_7 $$2Other$$aproteostasis
000294336 650_7 $$2Other$$astem cells
000294336 650_7 $$2Other$$aunfolded protein response
000294336 7001_ $$0P:(DE-He78)182bfcd26a8ff245bf9d349bed715e33$$avan Enk, Sizèd$$b1$$udkfz
000294336 7001_ $$aKildgaard, Sara$$b2
000294336 7001_ $$0P:(DE-He78)880900065fdfb634b00cd591b801ee42$$aSchlue, Silja$$b3$$udkfz
000294336 7001_ $$0P:(DE-He78)442ee8f54d846d943023a916889feb8e$$aGöttmann, Mona$$b4
000294336 7001_ $$0P:(DE-He78)f9436ab13c30938772ee246bd6920734$$aJennings, Lauren Victoria$$b5
000294336 7001_ $$0P:(DE-He78)06d81b4a485d027b97543964b7035573$$aBethke, Frederic$$b6$$udkfz
000294336 7001_ $$0P:(DE-He78)e490480a4e3d9a6a3a4f1408ca599590$$aMüller, Gabriele$$b7$$udkfz
000294336 7001_ $$aHerold-Mende, Christel$$b8
000294336 7001_ $$0P:(DE-HGF)0$$aPastor-Flores, Daniel$$b9
000294336 7001_ $$0P:(DE-He78)0d37cc734b95fed555f2244d6fee6320$$aSchneider, Martin$$b10$$udkfz
000294336 7001_ $$0P:(DE-He78)daaed5a5b968028e6e95d273150d5ab1$$aHelm, Dominic$$b11$$udkfz
000294336 7001_ $$aOstenfeld Larsen, Thomas$$b12
000294336 7001_ $$00000-0001-9046-4893$$aGoidts, Violaine$$b13$$eLast author
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