Aberrant basal cell clonal dynamics shape early lung carcinogenesis.

Summary

Carcinogen exposure induces non-neutral competition among airway basal cells, driving aberrant clonal expansion and migration that seed widespread preinvasive squamous lesions from a few highly mutated clones. Human multisite sequencing corroborates clonally related lesions across the bronchial tree, implicating clonal dynamics and fate shifts in field cancerization.

Key Findings

• Carcinogen exposure triggers non-neutral competition and aberrant clonal expansions among airway basal cells.
• A few highly mutated basal cell clones dominate most of the bronchial tree and give rise to preinvasive squamous lesions.
• Human multisite sequencing confirms clonally related preinvasive lesions across spatially distinct airway regions, supporting field cancerization.

Clinical Implications

Early detection and prevention strategies may need to target airway field cancerization and clonal fitness, guiding surveillance of multifocal lesions and informing chemopreventive approaches that modulate basal cell competition.

Limitations

• Preclinical model may not capture all human exposures or microenvironmental contexts.
• Limited quantitative data on human sample size and temporal evolution in patients.

Future Directions

Develop longitudinal, spatially resolved human airway sampling to map clonal evolution; test interventions that modulate basal cell competition or mutation-driven fitness to prevent lesion emergence.