Abstract
Small cell lung carcinoma (SCLC) is an aggressive neuroendocrine cancer that rapidly develops resistance to platinum-based chemotherapy. A key feature of SCLC is its ability to switch between neuroendocrine (NE) and non-neuroendocrine (non-NE) states, a process linked to therapeutic failure, yet the underlying mechanisms driving this plasticity remain incompletely understood. Here, we show that the translation initiation factor eIF6 is a critical regulator of non-NE transdifferentiation in SCLC. eIF6 expression is consistently upregulated in non-NE states across cell lines, mouse models, and patient samples, accompanied by global remodelling of the translational landscape. Mechanistically, eIF6 dissociates from ribosomes and interacts with the CD104-FAK complex, leading to MAPK pathway activation. Intervening eIF6 suppresses non-NE transdifferentiation and enhances SCLC chemotherapy sensitivity in vitro and in vivo. These findings position the eIF6-CD104-FAK axis as a prognostic marker and therapeutic target, offering a potential strategy to mitigate SCLC resistance.
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Data availability
The RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus under accession code GSE262597. The mass spectrometry proteomics data generated in this study have been deposited in the ProteomeXchange Consortium via the iProX partner repository under identifier PXD051035. The RNA-seq and proteomics data are fully available without restrictions. Processed data and all data supporting the findings of this study are provided in the Supplementary Information. Source data are provided with this paper.
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Acknowledgements
S.S. acknowledges grant support from the National Natural Science Foundation of China (grant no. 82473387) and from the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (grant no. Y2022JC002). L. Liu acknowledges financial support ZYGD18021 and ZYJC21002 from the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University. M.C. acknowledges grant support from Agence nationale de la recherche of France (grant no. ANR-23-CE14-0023). We thank Li Li, Fei Chen, Chunjuan Bao and Yang Deng from the Institute of Clinical Pathology, West China Hospital of Sichuan University for their technical support with histological staining. We thank Prof. Trudy G Oliver (Duke University, USA) for her generous suggestions for the RPM mouse model.
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H.P., Z.W. and M.W. are co-first authors and contributed equally. S.S. and H.P. designed the study. S.S., H.P., L.L., Z.W., M.W. and M.C. interpreted the data and wrote the original draft of the manuscript. H.P., Z.W., M.W., Z. D., K.L., performed RNA-seq and polysome profiling. H.P., Z.W., and M.W. performed ribosome mass spectrometry. H.P., Z.W. and M.W. performed the in vivo experiment. H.P., Z.D., Y.W., M.C., and Y.D. performed bioinformatics analysis. Y.L. performed protein structure analyses. S.S., H.P. and Z.W. performed patient sample multiplex staining and developed an image analysis pipeline. S.Song., X.Y., L.L. and W.W. performed histopathology analysis. Q.P. and L.Liu. provided administrative support and data resources, collected patient samples. S.S. supervised the overall study, provided strategic oversight and conceived the study.
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The authors declare the following competing interests: S. Shen reports personal fees from Agence nationale de la recherche (France), Krebsliga Schweiz (Switzerland), KWF Kankerbestrijding (Netherlands), Austrian Research Funding, Belgian Foundation against Cancer, Shenzhen Medical Academy of Research and Translation (China), and serving as an Associate Editor for Oncogenesis (Springer Nature, London, UK); M. Cerezo is a CSO for BiPer Therapeutics (Strasbourg, France) and reports personal fees from European Commission. The remaining authors declare no competing interests.
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Peng, H., Wang, Z., Wang, M. et al. Eukaryote initiation factor 6 modulates small-cell lung carcinoma plasticity via the integrin-FAK signaling axis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69899-8
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DOI: https://doi.org/10.1038/s41467-026-69899-8
