Abstract A17: Polyploid giant cancer cells lead to evolution of drug resistance in high-grade ovarian cancer

Abstract

Abstract Whole genomic duplications (WGD) have been reported in 37% to 56% of high-grade cancers. WGD leads to formation of polyploid giant cancer cells (PGCCs) with salient and atypical nuclear morphology noted by light microscopy. However, PGCCs are generally considered nonviable due to their inability to execute mitosis. We have recently reported that PGCCs are capable of generating mitosis-competent progeny cells via primitive amitotic division including budding, splitting, and burst. We have further demonstrated that PGCCs are part of the process of somatic reprogramming named the giant cell life cycle composed of four distinct but overlapping phases including initiation, self-renewal, termination, and stability. The giant cell life cycle resets the somatic cell from the mitotic cycle to stress-induced endoreplication cell cycle via WGD to form PGCCs. The PGCCs activate endogenous embryonic factors for the reprogramming, which leads to the birth of drug-resistant cells by clonal selection from newly generated heterogeneous cancer stem cells. However, the underlying genetic and epigenetic mechanisms during WGD remain unclear. By mapping DNA methylation and whole-genome sequencing, monitoring the telomere dynamics, and tracking the cellular and nuclear morphology using microscopic time-lapse imaging observations during the time course of giant cell life cycle, we hereby provide new evidence that the daughters cells derived from PGCCs have massive alterations at the whole-genome and epigenome levels. The reprogrammed resistant daughter cells are achieved, at least in part, by genomic instability via shortened telomeres. Targeting PGCCs and promoting their differentiation during the course of giant cell life cycle may represent a novel approach to intercept drug resistance. Citation Format: Na Niu, Xiaoran Li, Jun Yao, Anil Sood, Jinsong Liu. Polyploid giant cancer cells lead to evolution of drug resistance in high-grade ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A17.