Cell-state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer
Year: 2026
Type: article
Abstract: 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 ASCL1 high 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.
Source: Cell
Authors: Jun W. Kim, Christina M. Bebber, Yuqin Dai, Sarah Bopp, Anna Edenhofer, Albert M. Li, Thomas Rösner, Lena Berning, Ming Yang, Logan B. Leak, Jenny Stroh, Bindesh Shrestha, Ali T. Abdallah, Dimitrios Prymidis, Hernando J. Olivos, Maya Baron, Thuyen Nguyen, Yan Ting Shue, Yoko Nishiga, Alexandros P. Drainas, Andrea C. Chaikovsky, Krystina Szylo, Yang Li, Yun P. Kang, Parvathy Manoj, Alvaro Quintanal Villalonga, Charles M. Rudin, Gina M. DeNicola, Scott J. Dixon, Christian Frezza, Jiangbin Ye, Silvia von Karstedt, Julien Sage
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,400
Awards: G1545472099, G1740861664, G1773586305, G3864451752, Mechanisms of Cell Cycle and Cell Identity Regulation that Influence Sensitivity to Targeted Therapies, G6723498533, Stanford Cancer Institute, Modulating cysteine metabolism to induce cell death in small cell lung cancer, Novel therapeutic development for small cell lung cancer, Investigating molecular and cellular mechanisms of SCLC development to identify novel therapeutic strategies, Coordinating center for the NCI small cell lung cancer research consortium
OpenAlex ID: W7223291267