Characterization of Circulating MicroRNA Signatures During the Transition to Castration Resistance in Prostate Cancer

• Applicant: Pedro Pinto, Ph.D.
• Subject Area: Reproductive Medicine, Urology ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544003877

Prostate cancer (PCa) stands as a prominent global health concern and ranks fifth among the leading causes of cancer-related deaths in men. Its incidence escalates with age, affecting the majority of men over 65 years old. PCa can range from slow-growing to aggressive forms. A vital component of the male reproductive system, the prostate's growth is predominantly regulated by the androgen receptor (AR) and associated pathways. Aberrant AR activity results in uncontrolled proliferation of prostate cells, leading to the onset of PCa. Conventional treatments primarily involve androgen deprivation therapy (ADT), which aims to reduce testosterone levels, inhibiting AR activity and impeding cancer growth. PCa can progress to castration-resistant prostate cancer (CRPC), an aggressive malignancy that acquires hormone resistance and does not respond to ADT, resulting in poor survival rates. Timely detection is important for optimizing patient survival. While the prostate-specific antigen (PSA) test is the current diagnostic method for PCa, it lacks specificity as it can also detect benign prostate conditions and does not provide information about disease severity. MicroRNAs (miRs) are small molecules that regulate gene expression and can be found in blood and urine. Unique miR signatures have been identified in PCa and CRPC, offering the potential for detecting PCa and the onset of CRPC. However, our understanding of miR secretion by prostate cells and their expression during CRPC remains limited. To address this gap, we have developed an advanced dynamic 3D culture model, a microphysiological (MPS) model, allowing for the recreation and prolonged study of PCa physiology in a controlled environment. The primary objective of our proposal is to decipher miR signatures indicative of the transition of PCa cells from androgen-sensitive to androgen-insensitive conditions. Our goal is to recreate the progression of PCa cells to castration resistance within the MPS culture over an extended timeframe. Subsequently, the project aims to analyze the expression patterns of extracellular miRNAs released by PCa cells during this transition. We will also investigate the biological processes within the transformed cells and analyze their association with the identified miRs.

• DFG Programme: Research Grants