Gómez-López 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 Iñigo, Simons Benjamin D, Campbell Peter J, Janes Sam M
Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK.
Science. 2025 Jun 12;388(6752):eads9145. doi: 10.1126/science.ads9145.
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.
肺鳞状上皮内病变是肺鳞状细胞癌（LUSC）的前体。病变形成背后的细胞事件尚不清楚。我们使用一种无额外基因改变或细胞类型偏差的致癌物诱导的LUSC模型，发现致癌物暴露会导致基底细胞之间的非中性竞争、异常克隆扩张以及气道沿线的基底细胞迁移。最终，侵袭前病变由少数高度突变的克隆发展而来，这些克隆占据了大部分支气管树。对人类患者的多位点测序证实，在不同气道区域存在克隆相关的侵袭前病变。我们的研究确定了基底细胞克隆动力学的转变以及基底细胞命运的相关转变，是肺部场癌化的驱动因素。
