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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

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

Language: Английский

KSR1 regulates small-cell lung carcinoma tumor initiation and cisplatin resistance

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 26, 2024

Abstract Small-cell lung cancer (SCLC) has a dismal five-year survival rate of less than 7%, with limited advances in first line treatment over the past four decades. Tumor-initiating cells (TICs) contribute to resistance and relapse, major impediment SCLC treatment. Here, we identify Kinase Suppressor Ras 1 (KSR1), molecular scaffold for Raf/MEK/ERK signaling cascade, as critical regulator TIC formation tumor initiation vivo . We further show that KSR1 mediates cisplatin SCLC. While 50-70% control after 6-week exposure cisplatin, CRISPR/Cas9-mediated knockout prevents >90% ASCL1, NeuroD1, POU2F3 subtypes. KO significantly enhances ability decrease TICs via vitro extreme limiting dilution analysis (ELDA), indicating disruption toxicity responsible therapeutic initiation. The prevent resistant H82 xenograft supports this conclusion. Previous studies indicate ERK activation inhibits growth development. observe minimal effect pharmacological inhibition on no impact ELDA. However, mutational DEF domain, which interaction ERK, suggests is essential KSR1-driven resistance. These findings reveal key regulatory protein biology potential target across multiple Statement Implication Genetic manipulation small-cell reveals its contribution

Language: Английский