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.
| Original language | English |
|---|---|
| Pages (from-to) | 159-167 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 616 |
| Issue number | 7955 |
| Early online date | 5 Apr 2023 |
| DOIs | |
| Publication status | Published - 6 Apr 2023 |
Bibliographical note
This research was conducted using the UK Biobank Resource under application number 82693. This work was supported by the Mark Foundation ASPIRE I Award (grant 21-029-ASP), the Lung Cancer Research Foundation Grant on Disparities in Lung Cancer, Advanced Grant (PROTEUS, grant agreement no. 835297), CRUK EDD (EDDPMA-Nov21\100034) and a Rosetrees Out-of-round Award (OoR2020\100009). W.H. is funded by an ERC Advanced Grant (PROTEUS, grant agreement no. 835297), CRUK EDD (EDDPMA-Nov21\100034), The Mark Foundation (grant 21-029-ASP) and has been supported by Rosetrees. E.L.L. receives funding from the NovoNordisk Foundation (ID 16584), The Mark Foundation (grant 21-029-ASP) and has been supported by Rosetrees. C.E.W. is supported by a RESPIRE4 fellowship from the European Respiratory Society and Marie-Sklodowska-Curie Actions. C.L. is supported by the Agency for Science, Technology & Research, Singapore and the Cancer Research UK City of London Centre and the City of London Centre Clinical Academic Training Programme. M.A. is supported by the City of London Centre Clinical Academic Training Programme (Year 3, SEBSTF-2021\100007). K.C. is supported by the Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, the Chinese Academy of Medical Sciences (2021RU002), the National Natural Science Foundation of China (no. 82072566) and Peking University People’s Hospital Research and Development Funds (RS2019-01). T.K. receives grant support from JSPS Overseas Research Fellowships Program (202060447). S.-H.L. is supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (no. 2020R1A2C3006535), the National Cancer Center Grant (NCC1911269-3) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HR20C0025). L.H.S. receives grant support from the Berta Kamprad Foundation, the Swedish Cancer Society and the Swedish Research Council. R.M. and S.L. acknowledge funding from the Terry Fox Research Institute. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant number 211179/Z/18/Z) and receives funding from Cancer Research UK, the Rosetrees and the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. J. DeGregori, M.G., Y.E.M., D.T.M. and R.L.K. receive funding from the American Association for Cancer Research/Johnson&Johnson (18-90-52-DEGR), and J. DeGregori is supported by the Courtenay C. and Lucy Patten Davis Endowed Chair in Lung Cancer Research and a Merit Award from the Veteran’s Administration (1 I01 BX004495). M.G., Y.E.M., D.T.M. and R.L.K. were supported by the National Cancer Institute (NCI) RO1 CA219893. E.J.E.J. was supported by a NCI Ruth L. Kirschstein National Research Service Award T32-CA190216 and the Blumenthal Fellowship from the Linda Crnic Institute for Down Syndrome. C.I.T. acknowledges funding from UC Anschutz (LHNC T32CA174648). The work at the University of Colorado was also supported by NCI Cancer Center Support Grant P30CA046934. K. Litchfield is funded by the UK Medical Research Council (MR/P014712/1 and MR/V033077/1), the Rosetrees Trust and the Cotswold Trust (A2437) and Cancer Research UK (C69256/A30194). M.J.-H. is a CRUK Career Establishment Awardee has received funding from Cancer Research UK, IASLC International Lung Cancer Foundation, the National Institute for Health Research, the Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). His work is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041), and the Wellcome Trust (CC2041). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. C.S. is funded by Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; NovoNordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the Cancer Research UK-University College London Centre; Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US) (BCRF-22-157); Cancer Research UK Early Detection an Diagnosis Primer Award (grant EDDPMA-Nov21/100034); and The Mark Foundation for Cancer Research Aspire Award (grant 21-029-ASP). This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant number: SU2C-AACR-DT23-17 to S.M. Dubinett and A.E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835297). We acknowledge the PEACE Consortium (PEACE Consortium members are named below) for their expertise and support in putting together the healthy tissue sample cohorts. We thank the clinical and administrative team of the PEACE study for their assistance in data curation (S. Shepherd, Z. Tippu, B. Shum, C. Lewis, M. O’Flaherty, A. Lucanas, E. Carlyle, L. Holt, F. Williams); nursing and biospecimen coordinators for their assistance in sample curation (K. Edmonds, L. Grostate, K. Lingard, D. Kelly, J. Korteweg, L. Terry, J. Biano, A. Murra, K. Kelly, K. Peat, N. Hunter); A. H. -K. Cheung for assistance in pathology review; J. Asklin and C. Forsberg for logistical and technical assistance; staff at the Chang Gung Memorial Hospital for providing Chang Gung Research Database (CGRD) data; staff who provided support at the Flow Cytometry Unit, the Experimental Histopathology Unit, the Advanced Light Microscopy Facility, the Advanced Sequencing Facility and the Biological Resources Unit, especially N. Chisholm and Jay O’Brien, at the Francis Crick Institute; A. Yuen, A. Azhar, K. Lau, C. Schwartz, A. Lee and C. Rider for their logistical support for the human exposure study; and staff at the Centre d’expertise et de services Génome Québec for their sequencing services and support. Data for this study are based on patient-level information collected by the NHS, as part of the care and support of cancer patients. The data are collated, maintained and quality assured by the National Cancer Registration and Analysis Service, which is part of NHS England (NHSE). We extend our thanks to the skilled Cancer Registration Officers (CROs) within the National Disease Registration Service, who abstracted and registered the English tumour and molecular testing data.Data Availability Statement
Data availabilityDuplex-seq data for the PEACE and BDRE cohorts are available at the European Genome–Phenome Archive (EGA) with the identifier EGAS00001006951. Duplex-seq data generated from PEACE study samples during this study are not publicly available and restrictions apply to the availability of these data. Such Duplex-seq data are available through the Cancer Research UK and University College London Cancer Trials Centre (ctc.peace@ucl.ac.uk) for academic, non-commercial research purposes upon reasonable request and subject to review of a project proposal that will be evaluated by a PEACE data access committee, entering into an appropriate data access agreement and subject to any applicable ethical approvals. Duplex-seq data generated from the BDRE study are available through J. DeGregori (James.Degregori@cuanschutz.edu) for academic, non-commercial research purposes upon reasonable request, entering into an appropriate data access agreement and subject to any applicable ethical approvals. The Duplex-seq data for the BDRE and PEACE studies were generated using a larger panel of probes that covered approximately 50 kb of the genome, spanning hotspots frequently mutated in cancers. This full dataset has been provided for the 17 never-smoker individuals from the PEACE study. For all other samples, only data for the EGFR and KRAS regions queried are included in this manuscript. The RNA-seq data for the COPA study are available at the EGA with the identifier EGAS00001006966. De-identified participant data are available upon reasonable request to C.C. (christopher.carlsten@ubc.ca) for academic, non-commercial research purposes. Data availability is subject to a data access agreement and applicable ethical approvals. Mouse WGS data are available at the European Nucleotide Archive (ENA) with the identifier PRJEB58221 (ERP143287). Mouse RNA-seq data are available at the ENA with the identifier PRJEB59269 (ERP144330). Source data are provided with this paper.
Code availability
Code for analysis of epidemiology, RNA-seq and WGS data and processing of healthy lung tissue are available at Zenodo (https://doi.org/10.5281/zenodo.7705022).
Access to Document
- Hill_etal_N_Lung_Adenocarcinoma_Promotion_AAM
For the purpose of Open Access, the author has applied for a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. https://creativecommons.org/licenses/by/4.0/ Published in final edited form as: Nature. 2023 April 01; 616(7955): 159–167. doi:10.1038/s41586-023-05874-3.