Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Dr. Samikshan Dutta

Second Advisor

Dr. Kaustubh Datta

Abstract

Development of resistance mechanisms to the currently existing Androgen Receptor Signaling Inhibitor (ARSI) drugs has led to higher incidences of metastatic castration resistant prostate cancer (mCRPC) patients who progress in an AR-independent pathway. Compared to AR dependent mCRPC population, this increasing AR-independent mCRPC patients follow a highly aggressive disease with combined loss of tumor suppressors such as PTEN with RB1 inactivation and/or p53. AR-independent progression occurs either through a trans-differentiation program into neuroendocrine (NE) lineage, often referred as treatment-emergent neuroendocrine-like prostate cancer (t-NEPC) or via an AR-null non-NE processes, commonly addressed as double negative prostate cancer (DNPC). These AR-independent aggressive tumors show a likelihood for visceral metastasis to lungs and liver and presented with dismal survival outcomes and worst prognosis. These tumors are mostly resistant to taxane therapies and often treated with platinum-based chemotherapies in combination with etoposides with limited survival benefit. These tumors are associated with distinct epigenetic and transcriptional signatures belonging to neuronal gene signatures, thereby acquiring neuronal identities. Whether neuronal adaptation is important for the rapid growth and metastasis of these AR-independent genomic high-risk group mCRPC, is not yet defined. Moreover, whether adaptation of neural behaviors provides any survival advantage for these cells or is important for chemotherapy resistance remains unknown.

In the following study, we have carried out various high throughput analysis using RNA-seq, ChIP-seq and ATAC-seq to identify transcription factors (TF) that could be important for promoting the gene expression for neuronal characters in these AR-independent tumors. We found that Pax5 TF increases specifically during AR-independent stages and regulates neuronal gene expression involved in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are critical for strong cellular communications. Moreover, Pax5 depletion disrupts neurite-mediated cellular communication in these AR-independent cancer cells and reduces surface growth factor receptor activation, thereby, sensitizing them to docetaxel therapies. Moreover, hydroxymethylation of Pax5 promoter CpG islands favors Pbx1 binding to induce Pax5 expression in AR-independent stages.

Furthermore, our analysis reveals that Pax5 transcriptionally regulates various neuronal adhesion proteins such as NrCAM which is highly expressed during AR-independent progression and associated with clinically reduced survival. Our findings suggest that NrCAM is functionally significant for regulating cancer cells’ secretory properties to modulate the local tumor microenvironment. Additionally, NrCAM mediates a direct interaction between cancer cells and intra-tumoral nerves within the metastatic sites, thereby enhancing the growth and survival of AR-independent PCa. Therefore, targeting Pax5/NrCAM functional axis can be beneficial to block the highly metastatic growth and therapy resistance character in AR-independent PCa.

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2025 Copyright, the authors

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