KLF4 Promotes a KRT13+ Hillock-Like State in Lung Squamous Cell Carcinoma

Abstract Lung squamous cell carcinoma (LUSC) is a basal-like subtype of lung cancer with limited treatment options. While prior studies have identified tumor-propagating cell states in squamous tumors, further work is needed to elucidate the broader landscape of intra-tumoral heterogeneity within LUSC. Here, we employed SOX2-driven mouse models, organoid cultures, and single-cell transcriptomic analyses to uncover cell fate diversity within LUSC, identifying a KRT13+ hillock-like population of slower-dividing tumor cells characterized by immunomodulatory gene expression signatures. The tumor hillock-like state was conserved across multiple animal and human-derived models and was computationally predicted in the majority of human LUSCs as well as head and neck and esophageal squamous tumors. Analysis of the cellular origins of tumor hillock-like states indicated that lung club cells give rise to tumors with luminal hillock-like populations while basal-like tumor-propagating cells transition into basal hillock-like states, resembling lineage plasticity trajectories of the normal lung. Mechanistically, KLF4 promoted the KRT13+ hillock-like state and contributed to resistance to oxidative stress and platinum-based chemotherapy in vitro. Together, these results provide molecular insights into the lineage plasticity underlying intratumoral heterogeneity within LUSC, offering potential avenues for developing therapeutic strategies.