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KLF4 Promotes a KRT13+ Hillock-Like State in Lung Squamous Cell Carcinoma
Luke T Izzo1, Tony Reyes2, Srijan Meesala3
1Duke University Durham, North Carolina United States.
Cancer Research
|June 18, 2026
Summary
Researchers discovered a new slow-growing tumor cell state in lung squamous cell carcinoma (LUSC), termed the "hillock-like" state. This finding offers insights into tumor diversity and potential new therapeutic strategies for LUSC.
Area of Science:
- Oncology
- Cell Biology
- Genomics
Background:
- Lung squamous cell carcinoma (LUSC) is a challenging cancer subtype with limited therapeutic options.
- Understanding intra-tumoral heterogeneity is crucial for developing effective LUSC treatments.
- Previous research identified tumor-propagating cells but lacked a comprehensive view of LUSC cell diversity.
Purpose of the Study:
- To uncover the full spectrum of cell fate diversity within LUSC.
- To identify and characterize novel tumor cell populations in LUSC.
- To investigate the origins and regulatory mechanisms of LUSC cell states.
Main Methods:
- Utilized SOX2-driven mouse models and organoid cultures.
- Performed single-cell transcriptomic analyses to map cell diversity.
- Employed computational predictions to assess the prevalence of identified states in human cancers.
Main Results:
- Identified a KRT13+ "hillock-like" population of slow-dividing LUSC cells with immunomodulatory signatures.
- This hillock-like state was conserved across diverse models and predicted in human LUSC, head and neck, and esophageal squamous tumors.
- Demonstrated that lung club cells and basal-like tumor-propagating cells contribute to distinct hillock-like states, mirroring normal lung lineage plasticity.
- KLF4 was found to promote the KRT13+ hillock-like state and confer resistance to oxidative stress and chemotherapy.
Conclusions:
- Revealed significant cell fate diversity within LUSC, including a novel immunomodulatory hillock-like state.
- The findings highlight lineage plasticity as a key driver of intratumoral heterogeneity in LUSC.
- Identified KLF4 as a potential regulator of this state, suggesting new therapeutic targets for LUSC and related squamous cell carcinomas.
