Graduation Date

Fall 12-19-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Genetics, Cell Biology & Anatomy

First Advisor

Kaustubh Datta

Second Advisor

Benjamin Teply

Abstract

Advanced prostate cancer represents a particularly aggressive and challenging form of prostate cancer (PCa) that shows resistance to both traditional therapies, such as androgen deprivation therapy, and newer treatment modalities like hormone therapies and immunotherapies. For patients diagnosed with advanced stages of PCa, treatment options are limited, and chemotherapy is often the last line of defense. Unfortunately, chemotherapy can severely diminish the quality of life, particularly in older patients, due to its harsh side effects, including fatigue, immune suppression, and overall physical decline. Despite these challenges, researchers and clinicians remain focused on developing more effective and targeted treatments for patients with advanced prostate cancer. One promising area of research centers on Neuropilin-2 (NRP2), a transmembrane protein that has been identified as significantly upregulated during the progression of prostate cancer. Our research has demonstrated a strong correlation between NRP2 expression and the development of resistance to various therapies in advanced PCa. This resistance not only promotes the continued growth and spread of the tumor (metastasis) but also confers a protective effect, making cancer cells more resilient to treatment-induced cell death. Given the critical role NRP2 plays in both tumor progression and therapy resistance, we propose that targeting NRP2 could provide an effective therapeutic strategy for treating advanced prostate cancer. To get an understanding of the expression profile of NRP2 in high-grade prostate tumors, we stained tissue sections from the primary site of patients with high-grade prostate cancer with and without metastasis. Our findings suggested that NRP2 expression level at the primary tumor site could be an important predictor of disease metastasis. Therefore, understanding how this protein is expressed could play a crucial role in developing NRP2-targeted treatment options. To further explore this potential, we have investigated the mechanisms that regulate the expression of NRP2, focusing on how DNA methylation and the activity of the transcription factors Smad3 and Sox2, influence its expression. Through a series of experiments, we have discovered that the methylation status of the NRP2 promoter region along with the binding activity of Smad3, are key determinants of how much NRP2 is expressed. Smad3, an important downstream signaling molecule in the TGF-B pathway, appears to bind directly to regions within the NRP2 promoter, controlling its expression in metastatic castration resistant prostate cancer. In neuroendocrine like prostate cancer, SOX2, a well-known transcription factor involved in stem cell maintenance and cancer development, further enhances NRP2 expression through a mechanism independent of SMAD3. Our proposal aimed to expand on this knowledge by diving deeper into the interactions between Smad3, SOX2 and the NRP2 gene. Specifically, we investigated the binding dynamics of Smad3 together with it’s association with Sox2 at the regulatory regions of NRP2. This helped us better understand how NRP2 expression is controlled at the molecular level. By thus uncovering the precise mechanism of NRP2’s expression in advanced prostate cancer together with it’s expression pattern in patient tissues across various stages of disease progression, we hope to identify NRP2 as a viable target for future therapies, offering new treatment strategies for patients who currently have limited options.

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2025 Copyright, the authors

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