Determining the Mechanisms by which Exercise Exerts its Effect on Cancer

Exercise is broadly beneficial for human health and is one of the most potent modifiable lifestyle risk factors for many diseases, including cancer. Cancer is a highly prevalent disease and is one of the leading causes of death worldwide. While cancer incidence is a stochastic process, many factors influence the probability that an individual will develop cancer, including genetics, environmental exposures and lifestyle factors. An estimated two-thirds of cancer deaths in the U.S. can be attributed to modifiable risk factors such as smoking, diet and exercise. Exercise is the strongest positive modifiable risk factor and has been linked to almost all cancer types and stages of disease progression. Individuals who exercise more have reduced risk of developing cancer and improved clinical outcomes. However, even within a specific cancer type, tumors appear to respond differently to exercise. Indeed, the molecular mechanisms by which exercise exerts its effect on cancer outcomes are almost entirely unclear. My dissertation aims to fill this fundamental gap in our understanding of cancer etiology, uncovering how exercise affects diverse host and tumor molecular landscapes, as well as clinical outcomes. To enhance our molecular understanding of exercise oncology, I have separated my research into three chapters. These chapters cover a variety of study designs, including large cross-sectional patient cohorts, prospective longitudinal clinical trials, and experimental mouse studies. Each study design provides its own unique advantages, complementing each other and coming together to reveal novel insights into exercise oncology.In Chapter 1, I present the study of a large cross-sectional cohort of 5,150 patients with linked tumor genomic sequencing from 38 different cancer types and clinical annotation of post-diagnosis exercise dose and other important covariate lifestyle behaviors such as smoking, alcohol, and diet. Leveraging the large sample size and diversity of cancer types, we investigated both pan-cancer and ...