Lung adenocarcinoma promotion by air pollutants

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Item Type:	Article
Title:	Lung adenocarcinoma promotion by air pollutants
Creators Name:	Hill, W., Lim, E.L., Weeden, C.E., Lee, C., Augustine, M., Chen, K., Kuan, F.C., Marongiu, F., Evans, E.J., Moore, D.A., Rodrigues, F.S., Pich, O., Bakker, B., Cha, H., Myers, R., van Maldegem, F., Boumelha, J., Veeriah, S., Rowan, A., Naceur-Lombardelli, C., Karasaki, T., Sivakumar, M., De, S., Caswell, D.R., Nagano, A., Black, J.R.M., Martínez-Ruiz, C., Ryu, M.H., Huff, R.D., Li, S., Favé, M.J., Magness, A., Suárez-Bonnet, A., Priestnall, S.L., Lüchtenborg, M., Lavelle, K., Pethick, J., Hardy, S., McRonald, F.E., Lin, M.H., Troccoli, C.I., Ghosh, M., Miller, Y.E., Merrick, D.T., Keith, R.L., Al Bakir, M., Bailey, C., Hill, M.S., Saal, L.H., Chen, Y., George, A.M., Abbosh, C., Kanu, N., Lee, S.H., McGranahan, N., Berg, C.D., Sasieni, P., Houlston, R., Turnbull, C., Lam, S., Awadalla, P., Grönroos, E., Downward, J., Jacks, T., Carlsten, C., Malanchi, I., Hackshaw, A., Litchfield, K., DeGregori, J., Jamal-Hanjani, M. and Swanton, C.
Abstract:	A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development. Here we propose that environmental particulate matter measuring ≤2.5 μm ((PM2.5)), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM(2.5) levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM(2.5) air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.
Keywords:	Cancer Genomics, Non-Small-Cell Lung Cancer, Preclinical Research, Risk Factors, Animals, Mice
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	616
Number:	7955
Page Range:	159-167
Date:	6 April 2023
Additional Information:	Tom Kaufmann is a member of TRACERx Consortium. - Copyright © 2023. The Author(s), under exclusive licence to Springer Nature Limited.
Official Publication:	https://doi.org/10.1038/s41586-023-05874-3
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