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 S. Rodrigues
  • , Oriol Pich
  • , Bjorn 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, Ai Nagano, James R.M. 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 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 Houlston, Clare Turnbull, Stephen Lam, Philip Awadalla, Eva Grönroos, Julian Downward, Tyler Jacks, Christopher Carlsten, Ilaria Malanchi, Allan Hackshaw, Kevin Litchfield, Jason 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 A. Shaw, Joan Riley, Lindsay Primrose, Ekaterini Boleti, Heather Cheyne, Mohammed 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, Helen Shackleford, Madava Djearaman, Salma Kadiri, Gary Middleton, Angela Leek, Jack Davies Hodgkinson, Nicola Totten, Angeles Montero, Elaine Smith, Eustace Fontaine, Felice Granato, Helen Doran, Juliette Novasio, Kendadai Rammohan, Leena Joseph, Paul Bishop, Rajesh Shah, Stuart Moss, Vijay Joshi, Philip Crosbie, Fabio Gomes, Kate Brown, Mathew Carter, Anshuman Chaturvedi, Lynsey Priest, Pedro Oliveira, Colin R. Lindsay, Fiona H. Blackhall, Matthew G. Krebs, Yvonne Summers, Alexandra Clipson, Jonathan Tugwood, Alastair Kerr, Dominic G. Rothwell, Elaine Kilgour, Caroline Dive, Hugo J.W.L. Aerts, Roland F. Schwarz, Tom L. Kaufmann, Gareth A. Wilson, Rachel Rosenthal, Peter Van Loo, Nicolai J. Birkbak, Zoltan Szallasi, Judit Kisistok, Mateo Sokac, Roberto Salgado, Miklos Diossy, Jonas Demeulemeester, Abigail Bunkum, Aengus Stewart, Alexander M. Frankell, Angeliki Karamani, Antonia Toncheva, Ariana Huebner, Benny Chain, Brittany B. Campbell, Carla Castignani, Clare Puttick, Corentin Richard, Crispin T. Hiley, David R. Pearce, Despoina Karagianni, Dhruva Biswas, Dina Levi, Elena Hoxha, Elizabeth Larose Cadieux, Emma Colliver, Emma Nye, Felip Gálvez-Cancino, Foteini Athanasopoulou, Francisco Gimeno-Valiente, George Kassiotis, Georgia Stavrou, Gerasimos Mastrokalos, Haoran Zhai, Helen L. Lowe, Ignacio Garcia Matos, Jacki Goldman, James L. Reading, Javier Herrero, Jayant K. Rane, Jerome Nicod, Jie Min Lam, John A. Hartley, Karl S. Peggs, Katey S.S. Enfield, Kayalvizhi Selvaraju, Kerstin Thol, Kevin W. Ng, Krijn Dijkstra, Kristiana Grigoriadis, Krupa Thakkar, Leah Ensell, Mansi Shah, Marcos Vasquez Duran, Maria Litovchenko, Mariana Werner Sunderland, Michelle Dietzen, Michelle Leung, Mickael Escudero, Mihaela Angelova, Miljana Tanić, Olga Chervova, Olivia Lucas, Othman Al-Sawaf, Paulina Prymas, Philip Hobson, Piotr Pawlik, Richard Kevin Stone, Robert Bentham, Robert E. Hynds, Roberto Vendramin, Sadegh Saghafinia, Saioa López, Samuel Gamble, Seng Kuong Anakin Ung, Sergio A. Quezada, Sharon Vanloo, Simone Zaccaria, Sonya Hessey, Sophia Ward, Stefan Boeing, Stephan Beck, Supreet Kaur Bola, Tamara Denner, Teresa Marafioti, Thanos P. Mourikis, Thomas B.K. Watkins, Victoria Spanswick, Vittorio Barbè, Wei Ting Lu, Wing Kin Liu, Yin Wu, Yutaka Naito, Zoe Ramsden, Catarina Veiga, Gary Royle, Charles Antoine Collins-Fekete, Francesco Fraioli, Paul Ashford, Tristan Clark, Martin D. Forster, Siow Ming Lee, Elaine Borg, Mary Falzon, Dionysis Papadatos-Pastos, James Wilson, Tanya Ahmad, Alexander James Procter, Asia Ahmed, Magali N. Taylor, Arjun Nair, David Lawrence, Davide Patrini, Neal Navani, Ricky M. Thakrar, Sam M. Janes, Emilie Martinoni Hoogenboom, Fleur Monk, James W. Holding, Junaid Choudhary, Kunal Bhakhri, Marco Scarci, Martin Hayward, Nikolaos Panagiotopoulos, Pat Gorman, Reena Khiroya, Robert C.M. Stephens, Yien Ning Sophia Wong, Steve Bandula, Abigail Sharp, Sean Smith, Nicole Gower, Harjot Kaur Dhanda, Kitty Chan, Camilla Pilotti, Rachel Leslie, Anca Grapa, Hanyun Zhang, Khalid AbdulJabbar, Xiaoxi Pan, Yinyin Yuan, David Chuter, Mairead MacKenzie, Serena Chee, Aiman Alzetani, Judith Cave, Lydia Scarlett, Jennifer Richards, Papawadee Ingram, Silvia Austin, Eric Lim, Paulo De Sousa, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Harshil Bhayani, Lyn Ambrose, Anand Devaraj, Hema Chavan, Sofina Begum, Silviu I. Buderi, Daniel Kaniu, Mpho Malima, Sarah Booth, Andrew G. Nicholson, Nadia Fernandes, Pratibha Shah, Chiara Proli, Madeleine Hewish, Sarah Danson, Michael J. Shackcloth, Lily Robinson, Peter Russell, Kevin G. Blyth, Craig Dick, John Le Quesne, Alan Kirk, Mo Asif, Rocco Bilancia, Nikos Kostoulas, Mathew Thomas, James DeGregori, Mariam Jamal-Hanjani, Charles Swanton, Russell Driver

Research output: Contribution to journalArticlepeer-review

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 languageAmerican English
Pages (from-to)159-167
Number of pages9
JournalNature
Volume616
Issue number7955
DOIs
StatePublished - Jun 2023

Funding

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. 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.

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