DNA damage triggers squamous metaplasia in human lung and mammary cells via mitotic checkpoints

Epithelial transdifferentiation is frequent in tissue hyperplasia and contributes to disease in various degrees. Squamous metaplasia (SQM) precedes epidermoid lung cancer, an aggressive and frequent malignancy, but it is rare in the epithelium of the mammary gland. The mechanisms leading to SQM in t...

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Bibliographic Details
Published in:Cell death discovery 2023-01, Vol.9 (1), p.21-12, Article 21
Main Authors: Juan, Lucía San, Freije, Ana, Sanz-Gómez, Natalia, Jiménez-Matías, Beatriz, Pleguezuelos-Manzano, Cayetano, Sanz, J. Ramón, de Diego, Ernesto, Naranjo, Sara, Clevers, Hans, Gandarillas, Alberto
Format: Article
Language:English
Subjects:
631/136/142
692/699/67
Apoptosis
Biochemistry
Biomedical and Life Sciences
Carcinogens
Cell Biology
Cell Cycle Analysis
Chemotherapy
CHK1 protein
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Doxorubicin
Enoxacin
Epithelium
Genotoxicity
Hyperplasia
Life Sciences
Lung cancer
Malignancy
Mammary gland
Metaplasia
Nocodazole
Organoids
Paclitaxel
Polo-like kinase
Stem Cells
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Summary:Epithelial transdifferentiation is frequent in tissue hyperplasia and contributes to disease in various degrees. Squamous metaplasia (SQM) precedes epidermoid lung cancer, an aggressive and frequent malignancy, but it is rare in the epithelium of the mammary gland. The mechanisms leading to SQM in the lung have been very poorly investigated. We have studied this issue on human freshly isolated cells and organoids. Here we show that human lung or mammary cells strikingly undergo SQM with polyploidisation when they are exposed to genotoxic or mitotic drugs, such as Doxorubicin or the cigarette carcinogen DMBA, Nocodazole, Taxol or inhibitors of Aurora-B kinase or Polo-like kinase. To note, the epidermoid response was attenuated when DNA repair was enhanced by Enoxacin or when mitotic checkpoints where abrogated by inhibition of Chk1 and Chk2. The results show that DNA damage has the potential to drive SQM via mitotic checkpoints, thus providing novel molecular candidate targets to tackle lung SCC. Our findings might also explain why SCC is frequent in the lung, but not in the mammary gland and why chemotherapy often causes complicating skin toxicity.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-023-01330-3