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Peer-reviewedCC BY-NC-NDCell

Cell state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer

  • Jun W. Kim1,2,3
  • Christina M. Bebber1,2,4,5,3
  • Yuqin Dai6
  • Sarah Bopp1,2
  • Anna Edenhofer4,5
  • Albert M. Li7
  • Thomas Rösner1,2
  • Lena Berning1,2
  • Ming Yang8,9
  • Logan B. Leak10
  • Jenny Stroh4,5
  • Bindesh Shrestha11
21 more authors
  • Ali T. Abdallah5,12
  • Dimitrios Prymidis8,9
  • Hernando J. Olivos11
  • Maya Baron1,2
  • Thuyen Nguyen1,2
  • Yan Ting Shue1,2
  • Yoko Nishiga1,2
  • Alexandros P. Drainas1,2
  • Andrea C. Chaikovsky1,2
  • Krystina Szylo1,2,10
  • Yang Li7
  • Yun P. Kang13
  • Parvathy Manoj14,15
  • Alvaro Quintanal Villalonga14,15
  • Charles M. Rudin14,15
  • Gina M. DeNicola13
  • Scott J. Dixon10
  • Christian Frezza8,9
  • Jiangbin Ye7
  • Silvia von Karstedt4,5,16
  • Julien Sage1,2,17
17 affiliations
  1. 1Departments of Pediatrics, Stanford University, Stanford, CA, USA
  2. 2Departments of Genetics, Stanford University, Stanford, CA, USA
  3. 3These authors contributed equally
  4. 4Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  5. 5CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
  6. 6Sarafan ChEM-H, Stanford University, Stanford, CA, USA
  7. 7Department of Radiation Oncology, Radiation and Cancer Biology, Stanford University, Stanford, CA, USA.
  8. 8Institute for Metabolomics in Ageing, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  9. 9Institute of Genetics, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Faculty of Mathematics and Natural Sciences, Cologne, Germany
  10. 10Department of Biology, Stanford University, Stanford, CA, USA
  11. 11Waters Corporation, Milford, MA, USA
  12. 12University of Cologne, Faculty of Medicine, Institute of Medical Statistics and Computational Biology, Cologne
  13. 13Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, FL, USA
  14. 14Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  15. 15Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  16. 16Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  17. 17Lead contact
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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.

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Cite

BibTeXRIS
BibTeX
@article{kim2026cell,
  title = {{Cell state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer}},
  author = {Jun W. Kim and Christina M. Bebber and Yuqin Dai and Sarah Bopp and Anna Edenhofer and Albert M. Li and Thomas Rösner and Lena Berning and Ming Yang and Logan B. Leak and Jenny Stroh and Bindesh Shrestha and Ali T. Abdallah and Dimitrios Prymidis and Hernando J. Olivos and Maya Baron and Thuyen Nguyen and Yan Ting Shue and Yoko Nishiga and Alexandros P. Drainas and Andrea C. Chaikovsky and Krystina Szylo and Yang Li and Yun P. Kang and Parvathy Manoj and Alvaro Quintanal Villalonga and Charles M. Rudin and Gina M. DeNicola and Scott J. Dixon and Christian Frezza and Jiangbin Ye and Silvia von Karstedt and Julien Sage},
  journal = {Cell},
  year = {2026},
  month = oct,
  doi = {10.1016/j.cell.2026.09.045},
  url = {https://doi.org/10.1016/j.cell.2026.09.045},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Cell state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer
AU  - Jun W. Kim
AU  - Christina M. Bebber
AU  - Yuqin Dai
AU  - Sarah Bopp
AU  - Anna Edenhofer
AU  - Albert M. Li
AU  - Thomas Rösner
AU  - Lena Berning
AU  - Ming Yang
AU  - Logan B. Leak
AU  - Jenny Stroh
AU  - Bindesh Shrestha
AU  - Ali T. Abdallah
AU  - Dimitrios Prymidis
AU  - Hernando J. Olivos
AU  - Maya Baron
AU  - Thuyen Nguyen
AU  - Yan Ting Shue
AU  - Yoko Nishiga
AU  - Alexandros P. Drainas
AU  - Andrea C. Chaikovsky
AU  - Krystina Szylo
AU  - Yang Li
AU  - Yun P. Kang
AU  - Parvathy Manoj
AU  - Alvaro Quintanal Villalonga
AU  - Charles M. Rudin
AU  - Gina M. DeNicola
AU  - Scott J. Dixon
AU  - Christian Frezza
AU  - Jiangbin Ye
AU  - Silvia von Karstedt
AU  - Julien Sage
PY  - 2026
DA  - 2026/10/23
JO  - Cell
DO  - 10.1016/j.cell.2026.09.045
UR  - https://doi.org/10.1016/j.cell.2026.09.045
AB  - 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.
SN  - 0092-8674
SN  - 1097-4172
ER  -