Abstract 140: Polyaneuploid prostate cancer cells induced via chemotherapy have predominantly large, single nuclei

Abstract

Abstract 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.One important part of understanding how cells enter and exit that PACC state is to characterize the features of the PACC nuclei compared to “typical” PCa cells. Examining the distribution of DNA content and the size of individual nuclei allows us to infer the underlying mechanisms PCa cells use to enter the PACC state, such as cell fusion, endomitosis, endocycling, or mitotic slippage. Nuclear structure can further indicate what types of depolyploidization are possible, including neosis, polyploid mitosis, or uneven cell division. Thus, we developed a robust method to isolate nuclei from PACCs and used flow cytometry and immunofluorescence imaging to ascertain the nuclear content and size from whole PACC cells as well as the isolated nuclei. Analysis of nuclear features from both whole cells and isolated nuclei is necessary to resolve truly multinucleated cells from those that contain a single polylobulated nucleus.Our preliminary 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 were observed. This is in contrast with the opinion of many in the field, who believe that PACCs (and other variations of giant polyploid cancer cells) only exist in a multinucleated state. Continuation of these studies in various cancer cell lines and at sequential timepoints in the PACC state will deepen our understanding of how cancer cells evade systemic treatment and cause disease recurrence. Citation Format: Anna Gonye, Chi-Ju Kim, Kenneth Pienta, Sarah Amend. Polyaneuploid prostate cancer cells induced via chemotherapy have predominantly large, single nuclei [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 140.