Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer

• 成果类型: Article
• 署名作者: Ireland, Abbie S.; Xie, Daniel A.; Hawgood, Sarah B.; Barbier, Margaret W.; Zuo, Lisa Y.; Hanna, Benjamin E.; Lucas-Randolph, Scarlett; Tyson, Darren R.; Witt, Benjamin L.; Govindan, Ramaswamy; Dowlati, Afshin; Moser, Justin C.; Thomas, Anish; Puri, Sonam; Rudin, Charles M.; Chan, Joseph M.; Elliott, Andrew; Oliver, Trudy G.
• 署名单位: Duke University; Utah System of Higher Education; University of Utah; Washington University (WUSTL); Siteman Cancer Center; University System of Ohio; Case Western Reserve University; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); H Lee Moffitt Cancer Center & Research Institute; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09503-z
• 发表日期: 2025-11-06
• 关键词: lung-cancer; stem-cells; Heterogeneity; carcinoma; subtype; tumors; ascl1; sox2; inactivation; progression

摘要

Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes1, 2, 3, 4, 5, 6, 7, 8-9. The mechanisms driving neuroendocrine-tuft tumour heterogeneity and the origins of tuft-like cancers are unknown. Using multiple genetically engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine-tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovered unexpected transcriptional states, including an Atoh1+ state, and lineage trajectories underlying neuroendocrine-tuft plasticity. Uniquely in basal cells, the introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss and ASCL1 suppression, cooperates to promote tuft-like tumours. Transcriptomics of 944 human SCLCs revealed a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate notable conservation between cancer states and normal basal cell injury response mechanisms10, 11, 12-13. Together, these data indicate that the basal cell is a probable origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine-tuft heterogeneity, offering new insights for targeting lineage plasticity.