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Lung adenocarcinoma promotion by air pollutants

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posted on 2024-02-22, 17:15 authored by W Hill, EL Lim, CE Weeden, C Lee, M Augustine, K Chen, FC Kuan, F Marongiu, EJ Evans, DA Moore, FS Rodrigues, O Pich, B Bakker, H Cha, R Myers, F van Maldegem, J Boumelha, S Veeriah, A Rowan, C Naceur-Lombardelli, T Karasaki, M Sivakumar, S De, DR Caswell, A Nagano, JRM Black, C Martínez-Ruiz, MH Ryu, RD Huff, S Li, MJ Favé, A Magness, A Suárez-Bonnet, SL Priestnall, M Lüchtenborg, K Lavelle, J Pethick, S Hardy, FE McRonald, MH Lin, CI Troccoli, M Ghosh, YE Miller, DT Merrick, RL Keith, M Al Bakir, C Bailey, MS Hill, LH Saal, Y Chen, AM George, C Abbosh, N Kanu, SH Lee, N McGranahan, CD Berg, P Sasieni, R Houlston, C Turnbull, S Lam, P Awadalla, E Grönroos, J Downward, T Jacks, C Carlsten, I Malanchi, A Hackshaw, K Litchfield, TRACERx consortium, JF Lester, A Bajaj, A Nakas, A Sodha-Ramdeen, K Ang, M Tufail, MF Chowdhry, M Scotland, R Boyles, S Rathinam, C Wilson, D Marrone, S Dulloo, DA Fennell, G Matharu, JA Shaw, J Riley, L Primrose, E Boleti, H Cheyne, M Khalil, S Richardson, T Cruickshank, G Price, KM Kerr, S Benafif, K Gilbert, B Naidu, AJ Patel, A Osman, C Lacson, G Langman, James DeGregori, Mariam Jamal-HanjaniMariam Jamal-Hanjani, Charles SwantonCharles Swanton
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 development1. 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 PM2.5 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 PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

History

Author affiliation

Department of Genetics and Genome Biology, University of Leicester

Version

  • AM (Accepted Manuscript)

Published in

Nature

Volume

616

Issue

7955

Pagination

159 - 167

Publisher

Springer Science and Business Media LLC

issn

0028-0836

eissn

1476-4687

Copyright date

2023

Available date

2024-02-22

Spatial coverage

England

Language

eng