Cell-state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer
Menée à l'aide de lignées cellulaires, de xénogreffes de cancer du poumon à petites cellules sur des modèles murins ainsi que d'analyses transcriptomiques et métabolomiques, cette étude met en évidence l'influence de l'état métabolique des cellules cancéreuses sur le type de mort cellulaire induit (apoptose ou ferroptose) et démontre que combiner une déplétion de la cystéine et une inhibition de la synthèse des bioptérines BH4/BH2 réduit la croissance tumorale
Cellular heterogeneity and plasticity are hallmarks of cancer that contribute to tumor growth and therapy resistance. Here, we investigated metabolic heterogeneity in small cell lung cancer (SCLC), an aggressive cancer type with considerable plasticity between neuroendocrine (NE) and non-NE cellular states. Through integrated transcriptomic and metabolomic analyses, we identified a universal dependency on exogenous cysteine/cystine (Cys) across all NE/non-NE SCLC cell states. Notably, NE and non-NE cells with low ASCL1 transcription factor levels underwent ferroptosis upon Cys depletion, whereas ASCL1high cells underwent apoptosis while remaining resistant to ferroptosis. This ferroptosis resistance was driven by the direct transcriptional activation of GCH1 by ASCL1, resulting in increased levels of the antioxidants BH4/BH2. Accordingly, combined Cys depletion and inhibition of BH4/BH2 synthesis reduced tumor growth in patient-derived xenografts. These findings demonstrate that metabolic state influences cell-death susceptibility in SCLC and provide a rationale for therapeutic strategies that exploit these metabolic differences.
Cell , article en libre accès, 2026