Lung adenocarcinoma promotion by air pollutants

Hill, William;Lim, Emilia L;Weeden, Clare E;Lee, Claudia;Augustine, Marcellus;Chen, Kezhong;Kuan, Feng-Che;Marongiu, Fabio;Evans, Edward J;Moore, David A;Rodrigues, Felipe S;Pich, Oriol;Bakker, Bjorn;Cha, Hongui;Myers, Renelle;van Maldegem, Febe;Boumelha, Jesse;Veeriah, Selvaraju;Rowan, Andrew;Naceur-Lombardelli, Cristina;Karasaki, Takahiro;Sivakumar, Monica;De, Swapnanil;Caswell, Deborah R;Nagano, Ai;Black, James R M;Martínez-Ruiz, Carlos;Ryu, Min Hyung;Huff, Ryan D;Li, Shijia;Favé, Marie-Julie;Magness, Alastair;Suárez-Bonnet, Alejandro;Priestnall, Simon L;Lüchtenborg, Margreet;Lavelle, Katrina;Pethick, Joanna;Hardy, Steven;McRonald, Fiona E;Lin, Meng-Hung;Troccoli, Clara I;Ghosh, Moumita;Miller, York E;Merrick, Daniel T;Keith, Robert L;Al Bakir, Maise;Bailey, Chris;Hill, Mark S;Saal, Lao H;Chen, Yilun;George, Anthony M;Abbosh, Christopher;Kanu, Nnennaya;Lee, Se-Hoon;McGranahan, Nicholas;Berg, Christine D;Sasieni, Peter;Houlston, Richard;Turnbull, Clare;Lam, Stephen;Awadalla, Philip;Grönroos, Eva;Downward, Julian;Jacks, Tyler;Carlsten, Christopher;Malanchi, Ilaria;Hackshaw, Allan;Litchfield, Kevin;DeGregori, James;Jamal-Hanjani, Mariam;Swanton, Charles

2023-01-01

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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.