Cancer is a whole-body-level disorder rather than a mass at the tissue or cellular level. Most cancers take years to develop, busy becoming ‘the fittest’ by adapting to the environment and––to a certain extent––altering the environment in the body. Our group has a long-standing interest in understanding the multifaceted interactions between tumor and host at the Molecular, Cellular, and Organ levels. We believe the cross-system effects of cancer will be a critical aspect in clinical care, to ensure that we not only remove the malignant lesion but also restore a healthy system to prevent recurrence and other diseases. We currently focus on mechanisms mediated by cancer-secreted extracellular vesicles and their microRNA and protein cargo, for their role in systemic manifestations and comorbidities of breast cancer such as metabolic diseases, cachexia, and neurological disorders.