Mechanism of Action and Inflammatory Axis for Air Pollution Induced Non-Small Cell Lung Cancer with Professor Charles Swanton
William Harvey Day 2023 Keynote Lecture Spotlight
A mechanistic basis for non-small cell lung cancer (NSCLC) initiation in never smokers, a disease with high frequency EGFR mutations (EGFRm), is unknown. Air pollution particulate matter (PM) is known to be associated with the risk of NSCLC, however a direct cause and mechanism remain elusive. We analysed 463,679 individuals to address the associations of increasing 2.5um PM (PM2.5) concentrations with cancer risk. We performed ultra-deep profiling of 247 normal lung tissue samples, analysed normal lung tissue from humans and mice following exposures to PM, and investigated the consequences of PM in mouse lung cancer models. Increasing PM2.5 levels are associated with increased risk of EGFRm NSCLC in England, S.Korea and Taiwan and with increased risk of mesothelioma, lung, n UK Biobank (HR>1.1 for each 1ug/m3 PM2.5 increment). 18-53% of normal lung tissue samples harbour driver mutations in EGFR and KRAS in the absence of malignancy. PM promotes a macrophage response and a progenitor-like state in lung epithelium harbouring mutant EGFR. Consistent with PM promoting NSCLC in at-risk epithelium harbouring driver mutations, PM accelerates tumourigenesis in three EGFR or KRAS driven lung cancer models in a dose-dependent manner. Finally, we uncover an actionable inflammatory axis driven by IL1B in response to PM, in agreement with reductions in lung cancer incidence with anti-IL1B therapy. These data reveal a mechanistic basis for PM driven lung cancer in the absence of classical carcinogen-driven mutagenesis, reminiscent of models of tumour initiation and promotion proposed 70 years ago, providing an urgent mandate to limit air pollution, revealing opportunities for molecular targeted cancer prevention.
Professor Charles Swanton will deliver the Sir Anthony Dawson Lecture as part of Session 2 scheduled to run between 11.15am-12.55pm on Thursday 19 October.
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Charles completed his MBPhD training in 1999 at the Imperial Cancer Research Fund Laboratories and Cancer Research UK clinician scientist/medical oncology training in 2008. He is a senior group leader of the Cancer Evolution and Genome Instability Laboratory at the Francis Crick Institute and combines his research with clinical duties at UCLH, as a thoracic oncologist, focussed on how tumours evolve over space and time. His research branched evolutionary histories of solid tumours, processes that drive cancer cell-to-cell variation in the form of new cancer mutations or chromosomal instabilities, and the impact of such cancer diversity on effective immune surveillance and clinical outcome. Charles is chief investigator of TRACERx, a lung cancer evolutionary study and the national PEACE autopsy program.
Date: Thursday 19 October 2023, 9amVenue: Robin Brook Centre, West Smithfield CampusFull agenda: Please see the registration page.