Bioinspired Microphysiological Systems for in vitro Elucidation of Prostate Tumorigenic Progression and Application in Pre-clinical Therapeutic Evaluation

Abstract

Contrary to conventional belief, prostate cancer tumors are not merely uniform clusters of cancerous cells that undergo uncontrollable growth and migrate indiscriminately throughout the body. Instead, the prostatic tumor microenvironment is a highly intricate network of cancer and other tumor-supporting cell types that is characterized by a high degree of spatial and temporal heterogeneity in cell populations, tissue microarchitecture, vascularization, and therapeutic sensitivity. Despite this complexity, the traditional anti-cancer therapeutic development pipeline relies heavily on drastically oversimplified pre-clinical cancer models to predict drug safety and efficacy in patients. Consequently, nearly 97% of oncology therapeutic candidates fail during clinical trials, while many targetable mechanisms and biomarkers of tumorigenic progression are left undiscovered. To improve clinical translation in prostate cancer, this dissertation amalgamates an improved understanding of tumor pathophysiology with advances in biomaterial design and tissue engineering techniques to create bioinspired microphysiological systems that more accurately mimic patient disease in vitro. Chapter 1 elucidates tumorigenic progression and reviews both current therapeutic development processes and tools employed in the cancer tissue engineering field. Chapter 2 examines the pathophysiological tumor tissue stiffness range and introduces a mechanically tunable engineered prostate cancer tissue model to illuminate the role of matrix stiffness in prostate cancer. Chapter 3 expands the engineered prostate cancer tissue model to investigate the impact of varied cancer to stromal cell populations on aggressive versus indolent prostate cancer progression. Clinical relevancy is subsequently probed through a transcriptomic comparison to patient data. Finally, Chapter 4 reports the development of a microfluidic prostate tumor-on-a-chip platform that augments the engineered prostate cancer tissue model by incorporating dynamic flow conditions, additional tumor cell types, observation of cell migration, and differential drug exposure. To demonstrate the future utility of the prostate tumor-on-a-chip platform in anti-cancer therapeutic development, liposomal and solid nanoparticle drug delivery systems are evaluated on-chip. Finally, commentary on the recommended future directions for microphysiological system advancement and improved clinical translation in prostate cancer is provided.