Authors
Luke T Izzo, Tony Reyes, Srijan Meesala, Abbie S Ireland, Lisa B Earnest-Noble, Steven Yang, Hari Shankar Sunil, Xiao Chun Cheng, Nomi Tserentsoodol, Sarah B Hawgood, Carolyn Glass, Edward F Patz, Benjamin L Witt, Darren R Tyson, Kathryn A O'Donnell, Trudy G Oliver
Published in
Cancer research. Jun 18, 2026. Epub Jun 18, 2026.
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.
PMID:
42314152
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.
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