Tesa Severson1, Andries Bergman2, Wilbert Zwart3
(1) Netherlands Cancer Institute, Oncogenomics, Amsterdam, Netherlands. (2) Netherlands Cancer Institute, Oncogenomics, Amsterdam, Netherlands. (3) Netherlands Cancer Institute, Oncogenomics, Amsterdam, Netherlands.
Prostate cancer (PCa) progression is primarily driven by the androgen receptor (AR), a transcription factor central to tumorigenesis and disease development. Genomic studies reveal that AR binds predominantly to chromatin regions marked by H3K27ac, an epigenetic hallmark of active enhancers and promoters. While androgen deprivation therapy (ADT) initially suppresses AR signaling and induces tumor regression, adaptive mechanisms lead to metastatic castration-resistant PCa (mCRPC) and ultimately aggressive neuroendocrine differentiated tumors (NEPC). While treatment-emergent phenotypes are well studied, very limited molecular data from the treatment-naïve metastatic setting exists, which hinders understanding of intrinsic metastasis-specific features versus treatment-induced changes.
To address this, we analyzed genome-wide H3K27ac chromatin profiles from prostate cancer patient samples, in a time-course fashion allowing us to identify distinct signatures of H3K27ac trajectories during prostate development and progression. We included samples from normal prostate (n=6), primary PCa (n=6), treatment-naïve metastatic PCa (n=10), mCRPC (n=28), and neuroendocrine PCa (NEPC) (n=5). We identified clusters of epigenomic changes, including NEPC-specific loss of androgen response elements and metastatic-specific gains enriched in DNA repair, MTORC1 signaling, and MYC targets. These findings reveal that the transition from primary PCa to treatment-naïve metastasis is characterized by features associated with increased proliferation and aggressiveness, even without treatment-induced selection pressure.