Environmental and Lifestyle Cancer Risk Factors: Shaping Extracellular Vesicle OncomiRs and Paving the Path to Cancer Development

SIMPLE SUMMARY: In this study, we aim to shed light on a fascinating new aspect of cellular communication involving extracellular vesicles (EVs) and their cargo of microRNAs (EV-miRNAs). These EVs were once thought of as cellular waste but are now known to play a crucial role in transferring vital information between cells. We investigated how EV-miRNAs respond to various environmental and lifestyle factors and how this might be linked to the development and progression of cancer. By analyzing the associations between these factors and specific miRNAs related to common cancers (oncomiRs), we aim to better understand the complex regulatory networks of miRNAs in response to exogenous influences. The findings could revolutionize our understanding of cancer development and have important implications for future exposome studies in the research community. ABSTRACT: Intercellular communication has been transformed by the discovery of extracellular vesicles (EVs) and their cargo, including microRNAs (miRNAs), which play crucial roles in intercellular signaling. These EVs were previously disregarded as cellular debris but are now recognized as vital mediators of biological information transfer between cells. Furthermore, they respond not only to internal stimuli but also to environmental and lifestyle factors. Identifying EV-borne oncomiRs, a subset of miRNAs implicated in cancer development, could revolutionize our understanding of how environmental and lifestyle exposures contribute to oncogenesis. To investigate this, we studied the plasma levels of EV-borne oncomiRs in a population of 673 women and 238 men with a body mass index > 25 kg/m(2) (SPHERE population). The top fifty oncomiRs associated with the three most common cancers in women (breast, colorectal, and lung carcinomas) and men (lung, prostate, and colorectal carcinomas) were selected from the OncomiR database. Only oncomiRs expressed in more than 20% of the population were considered for statistical analysis. Using a Multivariate Adaptive Regression Splines (MARS) model, we explored the interactions between environmental/lifestyle exposures and EV oncomiRs to develop optimized predictor combinations for each EV oncomiR. This innovative approach allowed us to better understand miRNA regulation in response to multiple environmental and lifestyle influences. By uncovering non-linear relationships among variables, we gained valuable insights into the complexity of miRNA regulatory networks. Ultimately, this research paves the way for comprehensive exposome studies in the future.