LAUSR

Changes in the number of copies of the genome, i.e. changes in ploidy are widespread among cancer cells. Increased ploidy is thought to benefit cancer cells by conferring robustness against deleterious consequences of genomic instability. However, whether there are any potential costs associated with increased ploidy has not been sufficiently investigated. One hypothesis holds that high ploidy cells may exhibit increased sensitivity to limitations in resources, due to the extra energy required for the replication of a larger genome. To address this hypothesis, we developed an integrated in vitro and in silico system to investigate the response to glucose restriction in diploid and tetraploid cells. Near diploid (2N) SUM159 breast cancer cells were fused to generate an isogenic tetraploid (4N) cell line. 2N or 4N cells were plated with varying initial concentrations of glucose. Cells grew for five days and media was not refreshed, so cells depleted the glucose in the media until they eventually died. Throughout the experiments, glucose concentration was measured at 24 hour intervals, and images were taken at 8 hour intervals allowing quantification of the number of alive or dead cells over time. These in vitro data were then used as inputs to the in silico portion of our system, which consists of an Ordinary Differential Equation (ODE) model of cancer cell growth. ODE model parameters were estimated using the measured outputs from the in vitro experiments. Parameters estimated from the ODE model gave insight into differences between the 2N and 4N cell lines. We found that 4N cells outcompeted 2N cells at high glucose concentrations, due to their ability to divide more rapidly when glucose was abundant. However, 2N cells were able to outcompete 4N cells at lower glucose concentrations. The advantage of 2N cells at low glucose was not due to an increased proliferative capacity. Instead, 2N cells were more resistant to cell death when glucose was limited. Our next steps will be to expand our system to assess ploidy specific sensitivity to other resources, such as phosphate or oxygen. The ODE model we have developed allows us to identify resource conditions that will select for tumor cells based on ploidy. In future this knowledge can be used to suggest therapeutics that can modulate resource availability within tumors, in order to steer tumor evolution towards less aggressive phenotypes. Citation Format: Richard J. Beck, Didem Ilter, Ana P. Gomes, Noemi Andor. Detecting ploidy specific vulnerability to resource restriction: An integrated in vitro and in silico approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3171.