Airway hillocks are specialized, stratified squamous epithelial structures featuring luminal barrier cells supported by a dedicated basal stem cell population. In this issue of Cancer Research, Izzo and colleagues identify a distinct population of slow-cycling KRT13+ hillock-like tumor cells in lung squamous cell carcinoma, a cell state conserved across multiple squamous cell carcinoma (SCC) models. Mechanistically, KLF4 drives KRT13 expression, correlating with enrichment of potential therapeutic targets and resistance to platinum-based chemotherapy. By linking the physiologic epithelial barrier to therapeutic resistance, this study unlocks a previously uncharacterized mechanism underlying SCC biology. See related article by Izzo et al., p. 4472.
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