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Wang, Yu

University of British Columbia

Prostate cancer (PCa) is a multifaceted and heterogeneous disease that often progresses into distinct advanced lineages with treatment resistance following androgen deprivation therapy (ADT), posing significant clinical challenges. This thesis investigates the molecular mechanisms driving PCa progression, with a particular focus on transcription factors (TFs). A major limitation of current research is the inability to capture subtle transcriptional changes, leaving many TFs with critical roles in PCa progression undiscovered. To overcome this challenge, we developed a novel algorithmic method to comprehensively identify lineage-specific TFs, uncovering the TF landscape across prostatic adenocarcinoma (PRAD) and neuroendocrine prostate cancer (NEPC). Although it is well-established that NEPC arises from PRAD through neuroendocrine transdifferentiation, the detailed mechanisms underlying this transition remain poorly understood, with existing models providing only fragmented insights. To address these gaps, we conducted a longitudinal study on the identified lineage-TFs using the LTL331/331R transdifferentiation model. This unique model enabled us to propose a three-phase hypothesis—comprising de-differentiation, dormancy, and re-differentiation—that presents a macro-level framework outlining the key stages of PCa progression process. The later chapters focus on identifying NFIX as a key regulator in the de-differentiation stage, a critical barrier to subsequent progression. NFIX was found to be upregulated in response to ADT, and its inhibition significantly suppressed cell growth, particularly under ADT conditions, positioning NFIX as a promising therapeutic target to mitigate CRPC progression. Given the traditional challenges of targeting TFs, we developed a vivo-Morpholino (vMO) to inhibit NFIX and evaluate its therapeutic potential. The vMO effectively suppressed NFIX expression, leading to significant tumor growth inhibition in vivo, validating its potential as a novel therapeutic strategy for both ADT-sensitive and ADT-resistant prostate cancer. In summary, this thesis uncovers previously hidden lineage-specific TFs, proposes a three-phase model for PCa progression, and identifies NFIX as a critical regulator in dedifferentiation stage. By demonstrating that targeting NFIX with a vMO effectively inhibits tumor growth, we offer new therapeutic strategies for combating therapy-resistant prostate cancer. These findings provide a foundation for advancing treatment in both ADT-sensitive and ADT-resistant PCa, with the potential to improve patient outcomes.

Text

2025-03-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90518

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/