Oral Presentation 37th Lorne Cancer Conference 2025

Origins and signals of early lung tumourigenesis (114023)

Clare Weeden 1 2 , Maria Zagorulya 2 , William Hill 2 , Michelle Leung 2 3 , Tej Pandya 2 , Marcellus Augustine 2 3 , Rachel Scott 2 3 , Lydia Liu 2 , Emilia L Lim 2 , Eva Gronroos 2 , Nicholas M McGranahan 3 , Mariam Jamal-Hanjani 3 , Charles Swanton 2 3
  1. WEHI, Parkville, VIC, Australia
  2. Cancer Evolution And Genome Instability Laboratory, Francis Crick Institute, LONDON, United Kingdom
  3. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, LONDON, United Kingdom

Background

Recent studies confirm ‘normal’ tissue is replete with cells harbouring oncogenic mutations. Driver mutations are therefore understood as necessary but not sufficient for tumour formation. Understanding the multifactorial processes regulating tumour formation will allow early detection and cancer prevention strategies.

 

People with no history of smoking account for 25% of lung cancer cases and do not qualify for low-dose CT screening for early detection of lung cancer. We have recently identified that EGFR mutations, a common somatic driver of lung cancer in never-smokers, are present in lung tissue with no evidence of malignancy. Exposure to air pollution provoked macrophage-driven inflammation, ultimately promoting outgrowth of pre-existing EGFR-mutant alveolar cells to form adenocarcinomas (Hill, Lim, Weeden, Nature 2023). We now address which lung epithelial lineages can form EGFR-driven cancers and if signals of early tumourigenesis can be detected in patients. 

 

Methods

We used an adenoviral mouse model of lung adenocarcinoma to activate EGFRL858R in either airway or alveolar lineages and tracked the formation of cancers under the influence of air pollution using multiomic approaches. We analysed plasma proteomics from UK-based clinical trials to identify proteins elevated before lung cancer diagnosis.

 

Results

All lung lineages formed EGFR-driven adenocarcinomas that were molecularly indistinct and located in lung parenchyma. Live cell imaging and single cell multiomics revealed airway initiating cells moved into the alveoli, driven in part by WNT signals from the niche. Once in the alveoli, each lineage converged on an alveolar-like damage-associated cell state that preceded adenocarcinoma formation. Pollution exposure selected against tumour initiating basal cells due to IL-1b induced dormancy. Proteins associated with lung epithelial and myeloid cells were elevated in the plasma up to 5 years before lung cancer diagnosis in people enrolled in UK biobanks (n = ~250,000), including in those with no smoking history.

 

Conclusions

Our results suggests that the alveolar-like damage-associated cell state is highly conserved before overt malignancy. Signals of this state and the niche that supports it are detectable in plasma before lung cancer diagnosis, including those who would not qualify for lung cancer screening. We propose targeting this cell state could enable cancer prevention.