The Role of Axonal Pathways in the Development and Progression of Advanced Prostate Cancer
Creators: name: Wang, Jing
Publisher: name: Washington State University
Year: 2025

description: Prostate cancer (PC) is the most common non-skin malignancy and the second leading cause of cancer mortality in men in the United States. The risk of PC is influenced by a variety of factors, including age, genetics, lifestyle, and environmental factors. Most PCs are diagnosed in seniors by various assessments including prostate biopsy, prostate-specific antigen testing, digital rectal examination, magnetic resonance imaging, or health screening. There are multiple treatment options for PC patients, such as radical prostatectomy, radiation therapy, hormone therapy, androgen-deprivation therapy (ADT), and chemotherapy, with ADT being the primary care for PC. PC can be categorized into androgen-sensitive or androgen-insensitive types based on its responsiveness to testosterone stimulation and ADT. While localized PC can be effectively treated, the disease eventually progresses into an aggressive state where cancer cells develop the ability to resist treatments, leaving the disease incurable. Hence, there is a significant need for discovering novel therapeutics to treat advanced PC. There is increasing evidence suggesting that neural genes play a critical role in driving PC tumor growth and progression. Analysis of clinical patient samples suggests that the axon guidance receptors, neuropilin 2 (NRP2) and PlexinD1, are associated with disease progression and aggressive behavior in PC. We hypothesized that NRP2 and PlexinD1 upregulation may drive PC growth, progression, and metastasis. To address this hypothesis, we established stable cell lines with knockdown or overexpression of NRP2 or PlexinD1 in a panel of PC cell lines. Silencing of NRP2 or PlexinD1 significantly reduced cell proliferation, colony formation, sphere formation, migration, and invasion. Conversely, enforced expression of NRP2 or PlexinD2 enhanced these phenotypes. Notably, NRP2 and PlexinD1 also confer cell differentiation towards stem cell-like, basal, and neuroendocrine phenotypes. In vivo studies using subcutaneous and intracardiac xenograft models showed that NRP2 or PlexinD1 knockdown restricted tumor initiation, growth, and metastasis in advanced PC. Mechanistically, NRP2 and PlexinD1 as transcriptionally repressed by AR regulate tumor growth and progression through activation of receptor tyrosine kinase (RTK) pathways. Seeking a therapeutic approach, we designed a PlexinD1-targeted decoy protein, D1SP. D1SP treatment strikingly reduced cell and patient-derived organoid growth as well as cell migration and invasion. D1SP effectively inhibited tumor growth in mice. Perineural invasion (PNI) is known to associate with disease progression in PC. However, the in vitro models to mimic PNI are limited. Here, we developed a new 3D PNI in vitro assay and demonstrated an association of drug resistance with PNI in PC cells using this assay. Collectively, these studies reveal the functional and mechanistic roles of NRP2 and PlexinD1 in advanced PC and establish a new assay for in vitro characterization of PNI, providing new insights into the development of novel effective therapeutics for PC.