Abstract A028: Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells


 While localized prostate cancer (PCa) has a high treatment success rate, over 30,000 individuals in the United States and 350,000 men globally die each year from therapy resistant, metastatic PCa. A thorough understanding of the factors contributing to PCa recurrence following development of therapy resistance is acutely needed in order to develop efficacious treatments and disease-management strategies. Our group and others have identified a unique minority population of physically enlarged cancer cells with polyaneuploid genomes, termed polyaneuploid cancer cells (PACCs), in the tumors of patients with metastatic prostate cancer and in other tumor types. PACCs are the result of a polyaneuploid transition that occurs when aneuploid cancer cells experience environmental or therapeutic stress. These aneuploid cancer cells then pause their cell cycle after whole genome doubling to survive the environmental insult. Cancer cells in the PACC state appear to be quiescent and have an increased capacity for invasion/motility, an ability to endure in stressful or novel environments, and a propensity to undergo depolyploidization to re-establish the cancer cell population. We hypothesize that PACCs are critical players in prostate cancer therapy resistance and recurrence. We seek to better understand the life cycle of the PACC state in PCa in order to inform the design of new therapeutic strategies that prevent disease recurrence. Our data suggests that PCa cells in the PACC state tend to have a large polyploid single nucleus more frequently than multiple smaller, single nuclei, though both are observed at all timepoints in PACC recovery. Nuclear morphology and size certainly will impact the way that a cell organizes and utilizes its genome. Additionally, genome organization and stability have been demonstrated to be important factors/drivers of cancer development, progression, and recurrence. Importantly, epigenetic changes such as histone modifications can drastically affect chromatin condensation, which subsequently can alter the gene accessibility and transcription profile of a cell. We hypothesize that cancer cells in the PACC state have different histone modifications and different regions of accessible chromatin compared to parental cancer cells, and that these differences will also impact the gene expression of PACCs.
 Citation Format: Anna Gonye, Chi-Ju Kim, Ken Pienta, Sarah Amend. Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A028.