Sexual dimorphism and Tumour initiation, Ascertaining environmental and genetic Risk factors in Tumour evolution (START)

Patients with advanced, metastatic solid tumours have an overall survival of less than five years. We and others have shown that tumours harbour extensive intra-tumour heterogeneity (ITH) leading to ongoing tumour evolution, diverse therapy resistance mechanisms and an almost infinite adaptability - a significant challenge to curative therapy. As ITH increases over time, it is critical to intervene early in the disease course when the disease burden is at its lowest, ideally targeting and limiting cancer initiation. We have recently shown that air pollution acts independently of DNA mutagenesis to promote lung cancer in never-smokers (LCINS), a disease more common in females, via an immune cell activating macrophage IL-1B axis. EGFR mutant alveolar type 2 cells, present in the aging lung, respond to macrophage-derived IL-1B by adopting a progenitor-like, proliferative cell state that promotes tumorigenesis. These results indicate that air pollution conforms to the Berenblum model of tumour promotion, where an initiator, the initial EGFR mutation, and a promoter, in this case air pollution, both are required for tumorigenesis. This mutation-independent mechanism of tumour promotion indicates that opportunities may exist to prevent cancer by targeting inflammatory mediators across tissues. This proposal aims to identify, model, and manipulate local and systemic processes and intrinsic and extrinsic risk factors that affect tumour initiation and promotion in LCINS. Using normal human lung tissue, novel and established animal models, single-cell RNA-sequencing and immune-phenotyping approaches we will develop models to identify, investigate, target and modulate tumour intrinsic and extrinsic factors contributing to tumour initiation and promotion and elucidate the underlying, currently unknown biological causes for the observed sex-differences in LCINS. Ultimately, we endeavour to identify actionable factors to prevent LCINS initiation without adverse systemic effects.