Lung adenocarcinoma promotion by air pollutants
William Hill, Emilia L. Lim, Clare E. Weeden, Claudia Lee, Marcellus Augustine, Kezhong Chen, Feng‐Che Kuan, Fabio Marongiu, Edward J. Evans, David A. Moore, Felipe Silva Rodrigues, Oriol Pich, Björn Bakker, Hongui Cha, Renelle Myers, Febe van Maldegem, Jesse Boumelha, Selvaraju Veeriah, Andrew Rowan, Cristina Naceur‐Lombardelli, Takahiro Karasaki, Monica Sivakumar, Swapnanil De, Deborah R. Caswell, A. Nagano, James R. Black, Carlos Martínez‐Ruiz, Min Hyung Ryu, Ryan D. Huff, Shijia Li, Marie-Julie Favé, Alastair Magness, Alejandro Suárez‐Bonnet, Simon L. Priestnall, Margreet Lüchtenborg, Katrina Lavelle, Joanna Pethick, Steven J. Hardy, Fiona E. McRonald, Meng‐Hung Lin, Clara I. Troccoli, Moumita Ghosh, York E. Miller, Daniel T. Merrick, Robert L. Keith, Maise Al Bakir, Chris Bailey, Mark S. Hill, Lao H. Saal, Yilun Chen, Anthony M. George, Christopher Abbosh, Nnennaya Kanu, Se‐Hoon Lee, Nicholas McGranahan, Christine D. Berg, Peter Sasieni, Richard S. Houlston, Clare Turnbull, Stephen Lam, Philip Awadalla, Eva Grönroos, Julian Downward, Tyler Jacks, Christopher Carlsten, Ilaria Malanchi, Allan Hackshaw, Kevin Litchfield, J.F. Lester, Amrita Bajaj, Apostolos Nakas, Azmina Sodha-Ramdeen, Keng Ang, Mohamad Tufail, Mohammed Fiyaz Chowdhry, Molly Scotland, Rebecca Boyles, Sridhar Rathinam, Claire Wilson, Domenic Marrone, Sean Dulloo, Dean A. Fennell, Gurdeep Matharu, Jacqui Shaw, Joan Riley, Lindsay Primrose, Ekaterini Boleti, Heather Cheyne, Mohammed S. Khalil, Shirley Richardson, Tracey Cruickshank, Gillian Price, Keith M. Kerr, Sarah Benafif, Kayleigh Gilbert, Babu Naidu, Akshay J. Patel, Aya Osman, Christer Lacson, Gerald Langman
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 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. Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer