Club cells employ regeneration mechanisms during lung tumorigenesis

• DOI: 10.1038/s41467-022-32052-2
• Publication Date: 2022-08-05T10:07:30Z
• Authors: Yuanyuan Chen; Reka Toth; Sara Chocarro; Dieter Weichenhan; Joschka Hey; Pavlo Lutsik; Stefan Sawall; Georgios T. Stath...; Christoph Plass; Rocio Sotillo
• Keywords: Lineage (genetic); Cell of origin; CD24

Abstract The high plasticity of lung epithelial cells, has for many years, confounded the correct identification cell-of-origin adenocarcinoma (LUAD), one deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate cell origin Eml4-Alk LUAD, and show that Club Alveolar type 2 (AT2) cells give rise tumours. We focus on originated tumours find experience an epigenetic switch by which they lose their lineage fidelity gain AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories evolution are similar ones used during regeneration, suggesting leverage intrinsic regeneration mechanisms a tumour. Together, this study highlights role in LUAD initiation, identifies mechanism infidelity, confirms presence these features human tumours, unveils key conferring heterogeneity.