Cigarette smoke alters lung stem cells, resulting in different cancers

Chronic cigarette smoke exposure may change lung stem cells in ways that influence which types of lung cancer develop when cancer-driving genetic alterations occur.

Researchers using lung organoids – laboratory-grown models of lung tissue – found that chronic cigarette smoke exposure altered the epigenetic state and gene expression of lung cells. Subsequent genetic alterations in the organoids then influenced the type of lung cancer that developed when the cells were implanted into mice.

'What we have tried to do is model lung cancer from its very earliest stages,' said Dr Michelle Vaz, instructor in oncology at Johns Hopkins University in Baltimore, Maryland, and senior author of the study published in PNAS. 'What this tells us is that the genetic event alone is not sufficient.'

The researchers investigated non-small cell lung cancer (NSCLC), which accounts for most lung cancer cases. The paper notes that almost 80 percent of NSCLC is attributable to cigarette smoking and secondhand smoke exposure. They exposed mouse lung organoids to cigarette smoke condensate for six months. Cigarette smoke condensate is a mixture of chemicals and particles from cigarette smoke. The researchers found changes in gene activity, including reduced activity in pathways involved in inflammation, immune signalling and cell death. The exposure also changed the proportions and behaviour of stem and differentiated cells in the organoids.

They then introduced key lung cancer-driving genetic alterations, including a mutation in KRAS or the loss of TP53, before implanting the organoids into mice. Tumours formed only in mice implanted with smoke-exposed organoids carrying one of these genetic alterations; neither smoke exposure alone nor the genetic alterations in unexposed organoids produced tumours in this model.

The two different genetic alterations were associated with different NSCLC subtypes: organoids with KRAS mutations developed tumours with features of lung adenocarcinoma, while organoids lacking TP53 developed squamous cell carcinoma. Analyses also suggested that these tumour types arose from distinct stem-cell-derived states: one associated with bronchioalveolar stem cells and the other with basal stem cells.

The researchers also examined human-derived lung organoids and data from human lung tumours. The human organoids showed some changes similar to those observed in the mouse organoids. Analysis of human lung adenocarcinoma data also found lower expression of ZBP1 and related interferon-signalling genes in tumours with KRAS mutations than in tumours with TP53 mutations. These findings support the relevance of the results to human lung cancer, but do not establish that the same process causes cancer in people.

'What's exciting as a next step is whether we can learn more about these cell death pathways and whether some can be targeted, specifically in the KRAS versus TP53 setting,' Dr Vaz said. 'Can we combine that with epigenetic therapy or immunotherapy and help tumours that currently do not respond to treatment, respond better?'