Editors' ChoiceLUNG CANCER

A spring-like renewal in the lungs

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Science Translational Medicine  12 Feb 2020:
Vol. 12, Issue 530, eaba9020
DOI: 10.1126/scitranslmed.aba9020

Abstract

Epithelial cells with a low mutation burden expand after smoking cessation.

Smokers who succeed in quitting enjoy a considerable reduction in lung cancer risk over time. Science has struggled to explain why exactly that is. If cancer risk was solely determined by cumulative exposure to cigarette smoke, the duration of smoking cessation should not impact a person’s odds of getting cancer. It appears that kicking the habit has beneficial effects beyond putting an end to the constant mutagenic insult of cigarette smoke. A new paper on the mutational landscape of the bronchial epithelium now provides a glimpse of what these beneficial effects might be.

Yoshida et al. sequenced the genomes of 632 bronchial cells isolated from 16 individuals (children, people who had never smoked, and former and current smokers). As expected, mutational burden increased with age and smoking history, and cells that had been exposed to cigarette smoke displayed a characteristic mutational signature. Many cells harbored mutations in genes that are also frequently mutated in lung cancer—for example, TP53 and NOTCH1. A small subset of cells contained up to three driver mutations, showing that the presence of multiple oncogenic alterations is not exclusive to cancer cells. The most surprising finding, however, concerned the existence of a mysterious subpopulation of cells found predominantly in former smokers. These cells had few mutations—comparable to the mutation burden of cells in a never-smoker—and long telomeres, indicative of a history of low mitotic activity. This subpopulation was much smaller in current smokers, indicating that it expands upon smoking cessation.

Yoshida et al.’s discoveries have fascinating implications for our understanding of airway biology and cancer risk evolution. Although characterization of this cell population and the mechanisms by which it is safeguarded still need to be addressed, these results should provide renewed motivation to smokers who are considering quitting. Beyond the epidemiological data showing lung cancer risk reduction after smoking cessation, the present study suggests something more encouraging: the image of a regenerating lung that is being repopulated by epithelial cells that have somehow escaped the ravages of smoke exposure.

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