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Nouruzi, Shaghayegh

University of British Columbia

The treatment landscape of advanced prostate cancer continues to evolve, and the implementation of highly potent next-generation androgen receptor pathway inhibitors (ARPIs), such as Abiraterone and Enzalutamide, has prolonged the survival of men with advanced disease. However, prolonged treatment can alter the archetypal course of the disease, as highlighted by an increased incidence of aggressive disease variants that have lost their luminal identity. These variants often display histological dedifferentiation and alterations of the lineage. Clinically, these patients develop progression in the setting of low/non-rising serum prostate-specific antigen levels, elevated serum neuroendocrine markers, carcinoembryonic antigen levels, and/or metastases. Despite similar genetic profiles, only a few genetic variations, such as loss of RB1 and TP53, reliably distinguishes adenocarcinoma from neuroendocrine prostate cancer (NEPC), suggesting that epigenomic events are key contributing factors to cell plasticity and the acquired treatment resistance. While studies presented in this thesis and work published by others point to an epigenetic basis for emergent NEPC, there is still much unknown about the fundamental cellular and molecular interactions that bias lineage specification following ARPI therapies. We mapped genome-wide chromatin accessibility using an assay for transposase-accessible chromatin using sequencing across naturally occurring castration-resistance prostate cancer and NEPC cell lines. We found that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodelling to support the activation of stem cell-like/neuronal transcriptional programs. We discovered the DNA binding motif for the neural lineage transcription factor ASCL1 to be disproportionally enriched in accessible chromatin regions in t-NEPC compared to adenocarcinoma. Matched RNAseq data confirmed ASCL1 expression and transcriptional activity were upregulated in t-NEPC cell lines and patient tumours. Silencing ASCL1 prevented the emergence of NEPC in vitro and in vivo. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by the disruption of the Polycomb Repressive Complex-2 (PRC2) through the UHRF1/AMPK axis and changes the chromatin architecture in favour of the luminal phenotype. We showed that these epigenetic alterations are governed by ASCL1. Furthermore, this work provides proof of the principle of targeting ASCL1 to reverse neuroendocrine phenotype, support luminal conversion and re-addict tumours to ARPIs.

Text

2022-09-28

Attribution-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82780

Experimental Medicine

University of British Columbia

UBCV

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