Abstract A030: Characterizing cytotoxic therapy induced shifts in the cost-to-benefit ratio of high ploidy

Abstract

Abstract Analyses of intra-tumor heterogeneity across multiple cancer types suggest that tumor cell fitness declines once aneuploidy exceeds a certain limit. A significant difference in outcome between tumors above and below the limit however is only evident among therapy-naïve patients, not among patients who subsequently underwent cytotoxic therapy. Our hypothesis is that the context-dependent ambivalence of high ploidy is what accounts for both of these observations. On one hand, high ploidy ameliorates the deleterious effects of missegregation-induced genome-dosage imbalances, on the other hand a high ploidy cell has higher energetic demands as it has to replicate and express more genetic material. We performed a series of in-vitro and in-silico experiments to quantify both, (i) the costs and (ii) benefits of high ploidy. We developed and used mathematical models to predict differences in S phase duration between high and low ploidy cells (i), and to evaluate the possibility of mis-segregation induced population extinction (ii). Model predictions include critical curves that separate viable from non-viable populations as a function of their turnover- and mis-segregation rates. Missegregation- and turnover rates estimated for nine cancer types are then compared to these predictions for various biological assumptions. For (i), we evaluated three key building blocks of dNTP synthesis –PO4, O2 and Glucose– as candidate cell-extrinsic resources that cap ploidy in Glioblastoma and stomach cancers. We predict that at limiting dNTP concentrations, high-ploidy cells will take longer to replicate their DNA than low-ploidy cells. In-vitro experiments support these predictions showing that PO4 depletion imposes a higher fitness cost on near-tetraploid than on near-diploid breast cancer cells. For (ii), the majority of tumors across all nine cancer types had missegregation- and turnover rates that were within viable regions of the parameter space. When a dependency of mis-segregation rate on ploidy was introduced, ploidy states associated with low mis-segregation rates rendered MIE impossible at low turnover rates. Exposing a heterogeneous stomach cancer cell line to the microtubule-targeting drug Vinblastine confirmed that the high ploidy subpopulation had a fitness advantage. If our hypothesis is true, the implications are broad. It would explain vast differences in the extent of inter-tumor karyotype heterogeneity. It may contribute to explain why agents that block dNTP production work well in combination with DNA damaging agents. It would also explain differences in ploidy across different primary and metastatic sites. As solid tumors progress, resources in the tumor microenvironment become scarcer than the resources available in normal surrounding tissues. These resource-poor environments may push high-ploidy cells to leave the primary tumor and thrive at locations with abundant nutrients. Understanding the resource cost of high ploidy can help uncover its therapeutic vulnerabilities across tissue sites with versatile energy supplies. Citation Format: Noemi Andor, Ana Gomes, Gregory Kimmel, Andriy Marusyk, Richard Beck, Daria Miroshnychenko, Andrew Schultz, Samuel Bakhoum, Philipp Altrock, Thomas Veith. Characterizing cytotoxic therapy induced shifts in the cost-to-benefit ratio of high ploidy [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A030.