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

These files are processed single-cell RNA-seq data (including genetic barcoding results for lineage tracing) in Seurat, SingleCellExperiment, or AnnData format. The data were generated and used to support the basal cell of origin for small cell lung cancer and an explanation of phenotypic plasticity between neuroendocrine and tuft-like lineages in a article accepted for publication in Nature (Ireland et al., 2025). These data files are used by the code available within the TGOliver-lab GitHub manuscript repository to generate the figures published in the article.

Summary

Neuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by 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 outcomes. 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 uncover unexpected transcriptional states and lineage trajectories underlying neuroendocrine–tuft plasticity. Uniquely in basal cells, introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss, and ASCL1 suppression, cooperate to promote tuft-like tumours. Transcriptomics of 944 human SCLCs reveal a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate remarkable conservation between cancer states and normal basal cell injury response mechanisms. Together, these data suggest that the basal cell is a likely origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine–tuft heterogeneity—offering new insights for targeting lineage plasticity.