Diverse routes of Club cell evolution in lung adenocarcinoma

Summary The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we address the cell-of-origin of LUAD, by employing lineage-tracing mouse models combined with a CRISPR/Cas9 system to induce an oncogenic Eml4-Alk rearrangement in virtually all epithelial cell types of the lung. We find that Club cells give rise to lung tumours with a higher frequency than AT2 cells. Based on whole genome methylome, we identified that tumours retain an ‘epigenetic memory’ derived from their originating cell type but also develop a tumour-specific pattern regardless of their origin. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, providing a link between lung regeneration and cancer initiation. On both routes, tumours lose their Club cell identity and gain an AT2- like phenotype. Together, this study highlights the role of Club cells in LUAD initiation and unveils key mechanisms conferring LUAD heterogeneity.