KLF4 promotes a KRT13+ hillock-like state in squamous lung cancer.

Lung squamous cell carcinoma (LUSC) is basal-like subtype of lung cancer with limited treatment options. While prior studies have identified tumor-propagating cell states in squamous tumors, the broader landscape of intra-tumoral 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 tumor cells characterized by immunomodulatory gene expression signatures. The tumor hillock-like state is conserved across multiple animal models and is present in the majority of human LUSCs as well as head and neck and esophageal squamous tumors. Our findings shed light on the cellular origins of lung hillock-like states: normal club cells give rise to tumors with luminal hillock-like populations, while basal-like tumor-propagating cells transition into basal hillock-like states, resembling homeostatic cellular responses to lung injury. Mechanistically, we identify KLF4 as a key transcriptional regulator of the hillock-like state, both necessary and sufficient to induce KRT13 expression. Together, these results provide new molecular insights into cell fate plasticity that underlies intra-tumoral heterogeneity in LUSC, offering potential avenues for new therapeutic strategies.