UCLA

Prostate cancer is the leading cause of cancer-related death in non-smoking males. Key factors that contribute to prostate mortality include high incidence and poor survival after recurrence. Delineating mechanisms of prostate cancer initiation, progression, and therapy resistance is required to reduce mortality from the disease. Aging is the largest risk factor for prostate cancer initiation, yet age-related changes to the cell types that can initiate prostate cancer are poorly defined. Cells that survive treatment enable prostate cancer progression and therapy resistance, in many cases, by transitioning from therapy-responsive to therapy-resistant lineages. However, how lineage identity is regulated in the prostate is not fully understood. Furthermore, uncovering vulnerabilities of cells that survive treatment remains an area of active research. In this dissertation, I explore the effects of aging on the cell types of the prostate and identify an age-related expansion of progenitor-enriched prostate epithelial cells as one mechanism by which aging could increase prostate cancer incidence. In addition, I define metabolic regulation of lineage transitions, which enable therapy resistance, and identify targetable treatment-induced metabolic vulnerabilities. These findings yield new strategies to prevent prostate cancer initiation and reduce death from resistant disease.