It is well known that a significant number of cancer cases are influenced by modifiable behavioral, environmental, and occupational factors. While some of these factors promote cancer by inducing oncogenic mutations, emerging evidence suggests that these mutations alone are not sufficient to drive tumor formation. Indeed, researchers have found oncogenic mutations in lung cancer driver genes within histologically normal lung tissue of individuals without the disease. In a previous ASPIRE award, Charles Swanton showed that exposure to air pollution was linked to macrophage-driven inflammation, wherein air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This promoted a progenitor-like cell state within lung epithelial cells with preexisting mutations that drove cancer formation. These results are part of a growing body of evidence suggesting that many cancer risk factors and environmental carcinogens alter tissue microenvironments and the properties of pre-existing mutant cells to allow for cancer initiation without directly causing mutations in a process termed “tumor promotion”.
In this ASPIRE II award, Swanton will team up with Sherene Loi to expand this work to encompass broader categories of environmental exposures and different tumor types. They will delve deeper into the mechanisms by which various risk and protective factors modulate the fate of tumor-initiating cells through non-mutagenic pathways. In addition to continuing the work on pollutants and lung cancer, they will investigate the well-documented but poorly understood protective effect of pregnancies and breastfeeding against breast cancer incidence. The Loi lab has shown that pregnancy leads to the remodeling of the mammary gland through the influx of CD8+ tissue-resident memory T cells, offering protection against breast cancer. These discoveries underscore the interplay between environmental factors, immune response, and cancer initiation and suggest promising avenues for clinical intervention.
The project will employ a range of advanced methodologies, including functional in vivo and ex vivo systems, deep sequencing, clinical questionnaires, and immune profiling, to investigate the effects of risk factors such as inhaled pollutants (e.g., vaping, microplastics, wood-smoke) and protective factors like pregnancy on tumor development. Furthermore, the project aims to explore how risk factor-induced tissue remodeling impacts the likelihood of tumor initiation by analyzing the variant allele frequency of known oncogenic mutations and assessing tissue architecture disruption in healthy tissue cohorts. In-depth immune profiling of normal tissue from clinical cohorts, along with studies utilizing mouse models, will allow for the identification of key molecular regulators of immunity in cancer initiation. Through the study of different environmental factors, changes in the immune microenvironment, and preexisting mutations, the project endeavors to gain a deeper understanding of tumor formation and identify potential interventions with the goal of developing effective strategies for the molecular prevention of cancer in high-risk individuals.