Abstract 2413: Unstable genomes and the average cancer cell

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The high degree of multi-level heterogeneity represents a key challenge for cancer research. Despite its importance, both the theoretical concepts and appropriate tools for proper quantitative analysis are underdeveloped. Specifically, the characterization of heterogeneity in cancer cell populations of different genomic stabilities, and its effect on systems dynamics are poorly understood. We use a single-cell and population-based assays to describe an instability-mediated mechanism where genome heterogeneity drastically affects cell growth, and cannot be accurately measured using conventional averages. First, we show that most unstable cancer cell populations exhibit high levels of karyotype heterogeneity, where it is difficult, if not impossible, to karyotypically clone cells. Second, by comparing stable and unstable cell populations, we show that instability-mediated karyotype heterogeneity leads to growth heterogeneity, where outliers dominantly contribute to population growth and exhibit shorter cell cycles. Predictability of population growth is more difficult for heterogeneous cell populations than for homogenous cell populations. Since “outliers” play an important role in cancer evolution, where genome instability is the key feature, averaging methods used to characterize cell populations are misleading. We conclude: 1) the karyotype cannot be cloned when genome instability is high, and caution is needed for single cell analysis for cell populations that are not genetically identical; 2) the “average” cancer cell does not exist, as the statistical mean does not accurately describe systems behavior, especially genome instability is high; and 3) single cell analysis is needed when cells are not genomically identical. Our results not only provide an explanation for population heterogeneity but also explain how genome-level heterogeneity contributes to drug resistance and cancer evolution. Note: This abstract was not presented at the meeting. Citation Format: Batoul Abdallah, Joshua B. Stevens, Steven Horne, Guo Liu, Henry HQ Heng. Unstable genomes and the average cancer cell. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2413. doi:10.1158/1538-7445.AM2014-2413