Code and data associated with Izzo et al journal submission

Lung squamous cell carcinoma (LUSC) is a basal-like subtype of lung cancer with limited treatment options. While prior studies have identified tumour-propagating cell states in squamous tumours, the broader landscape of intra-tumoural heterogeneity within LUSC remains poorly understood. Here, we employ Sox2-driven mouse models, organoid cultures, and single-cell transcriptomic analyses to uncover previously unrecognized levels of cell fate diversity within LUSC. Specifically, we identify a KRT13+ hillock-like population of slower-dividing tumour cells characterized by immunomodulatory gene expression signatures. The tumour hillock-like state is conserved across multiple animal and human-derived models and is present in the majority of human LUSCs as well as head and neck and esophageal squamous tumours. Our findings shed light on the cellular origins of tumour hillock-like states: lung club cells give rise to tumours with luminal hillock-like populations, while basal-like tumour-propagating cells transition into basal hillock-like states, resembling lineage plasticity trajectories of the normal lung. Mechanistically, KLF4 promotes KRT13, a broadly conserved hillock-like state with enrichment of potential therapeutic targets, and resistance to platinum-based chemotherapy. Together, these results provide molecular insights into the lineage plasticity underlying intra-tumoural heterogeneity within LUSC, offering potential avenues for new therapeutic strategies.