Aberrant basal cell clonal dynamics shape early lung carcinogenesis

• 成果类型: Article
• 署名作者: Gomez-Lopez, Sandra; Alhendi, Ahmed S. N.; Przybilla, Moritz J.; Bordeu, Ignacio; Whiteman, Zoe E.; Butler, Timothy; Rouhani, Maral J.; Kalinke, Lukas; Uddin, Imran; Otter, Kate E. J.; Chandrasekharan, Deepak P.; Lebrusant-Fernandez, Marta; Shurr, Abigail Y. L.; Durrenberger, Pascal F.; Moore, David A.; Falzon, Mary; Reading, James L.; Martincorena, Inigo; Simons, Benjamin D.; Campbell, Peter J.; Janes, Sam M.
• 署名单位: University of London; University College London; Wellcome Trust Sanger Institute; Universidad de Chile; University of London; University College London; University of London; University College London; University of London; University College London; Cancer Research UK; University of London; University College London; University College London Hospitals NHS Foundation Trust; University of London; University College London; University of Cambridge; University of Cambridge; University of Cambridge; University of Cambridge; University of London; University College London; University College London Hospitals NHS Foundation Trust
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13563
• DOI: 10.1126/science.ads9145
• 发表日期: 2025-06-12
• 关键词: airway stem-cells; somatic mutation; cancer; epithelium; distinct; lineage; PERSPECTIVE; homeostasis; alveolar

摘要

Preinvasive squamous lung lesions are precursors of lung squamous cell carcinoma (LUSC). The cellular events underlying lesion formation are unknown. Using a carcinogen-induced model of LUSC with no added genetic hits or cell type bias, we found that carcinogen exposure leads to non-neutral competition among basal cells, aberrant clonal expansions, and basal cell mobilization along the airways. Ultimately, preinvasive lesions developed from a few highly mutated clones that dominate most of the bronchial tree. Multisite sequencing in human patients confirmed the presence of clonally related preinvasive lesions across distinct airway regions. Our work identifies a transition in basal cell clonal dynamics, and an associated shift in basal cell fate, as drivers of field cancerization in the lung.