Aberrant basal cell clonal dynamics shape early lung carcinogenesis

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-05-01 DOI:10.1126/science.ads9145

Sandra Gómez-López, Ahmed S. N. Alhendi, Moritz J. Przybilla, Ignacio Bordeu, Zoe E. Whiteman, Timothy Butler, Maral J. Rouhani, Lukas Kalinke, Imran Uddin, Kate E. J. Otter, Deepak P. Chandrasekharan, Marta Lebrusant-Fernandez, Abigail Y. L. Shurr, Pascal F. Durrenberger, David A. Moore, Mary Falzon, James L. Reading, Iñigo Martincorena, Benjamin D. Simons, Peter J. Campbell, Sam M. Janes

引用次数: 0

Abstract

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 find that carcinogen exposure leads to non-neutral competition among basal cells, aberrant clonal expansions, and basal cell mobilization along the airways. Ultimately, preinvasive lesions develop from a few highly mutated clones that dominate most of the bronchial tree. Multi-site sequencing in human patients confirms 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.

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异常基底细胞克隆动力学影响早期肺癌的发生

肺浸润前鳞状病变是肺鳞状细胞癌（LUSC）的前兆。病变形成背后的细胞事件尚不清楚。我们使用了一个没有添加基因撞击或细胞类型偏倚的致癌物质诱导的LUSC模型，发现致癌物质暴露导致基底细胞之间的非中性竞争、异常克隆扩增和基底细胞沿气道的动员。最终，侵袭前病变由几个高度突变的克隆发展而来，这些克隆主宰了大部分支气管树。人类患者的多位点测序证实了在不同气道区域存在克隆相关的侵袭前病变。我们的工作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，作为肺场癌的驱动因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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