Abstract 3774: Elevated cancer evolution dynamics: Emergence of polyploid cancer cells in response to multimodal therapy as an adaptive response on both individual and collective levels

Field: Biochemistry, Genetics and Molecular Biology (Life Sciences)

Abstract Polyploidy has been often associated with poor prognosis and has been described to some extent in histological samples for most types of solid tumors. In cancer biology, it has been proposed to induce the gain of a stem-like phenotype and drive tumor progression by increasing the potential for cellular transformation. Experiments with chemotherapy gradients in our engineered microfluidic device with prostate cancer cell lines exhibited a stiff polyploidy distribution pattern of heterogeneous cell populations across the gradient. This demonstrates the generation of polyploid giant cancer cells (PGCCs) is an emergent response to high doses across the microfluidic drug stress landscape. Furthermore, in these experiments we observed polyploidization events occurring concurrently with the development of drug resistance and delayed relapse by non-polypoidal cell budding off from PGCCs leading to a complete repopulation, even in the high-dose areas of the array. Recent publications suggest polyploidy might play a crucial role in resistance to chemo-, hormone- and radio-therapy across most solid tumors investigated, thus independent of the therapy’s mechanism of action. To confirm these findings, we conducted experiments in conventional cell culture using different chemotherapeutic agents and ionizing radiation in several cell lines and confirmed the development of polyploidy was a common feature among them. Although these data supporting the association of polyploidy with resistance are extensive, the effects of these therapies on tumor heterogeneity and the cancer stem niche remains unknown. Different molecular mechanisms, such as mitotic slippage, aborted cytokinesis, endo-replication or cell fusion can lead to polyploidy. We hypothesize a subset of polyploid cells with stem-like features may be the reservoir of therapeutic resistance in cancer. In this work we focused on the characterization of this subset of cells within the tumor leading to the polyploid-stem phenotype, particularly the subpopulation with potential to reverse polyploidy and repopulate tumor heterogeneity after therapy. In order to establish causality and chronology of these phenomena, as well as quantify the complex population dynamics involved in this process, we engineered several cell lines from various common types of solid tumors with two fluorescence biosensors enabling simultaneous monitoring of SOX2/OCT4 activity and cell cycle status at the single-cell level using high-throughput confocal videomicroscopy. The emergence of polyploid cancer cells in response to multimodal therapy as an adaptive response on both individual and collective levels may be a hallmark of elevated cancer evolution dynamics and constitutes a promising potential target to prevent relapse. Citation Format: Gonzalo Torga, Ke-Chih Lin, Kayla Myers, Kimberly Smith, Robert H. Austin, Kenneth J. Pienta. Elevated cancer evolution dynamics: Emergence of polyploid cancer cells in response to multimodal therapy as an adaptive response on both individual and collective levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3774.