Abstract 4535: Tumor cell division rate heterogeneity explains in vitro clonal dominance

The cells that make up a tumor exhibit large phenotypic and genotypic variation, which strongly influences the effectiveness of cancer therapy. A typical manifestation of intratumor heterogeneity is the presence of a few clones that represent most of the tumor population, i.e. clonal dominance. Such heterogeneity could potentially be caused by the occurrence of different ratios of cancer stem cells and differentiated cells per clone, or, alternatively, clonal dominance may be caused by heterogeneity of division rates between clones. Previously published work, applying lineage tracing with genetic barcodes to in vitro iterated growth and passage experiments demonstrated that clonal dominance was accompanied by clone loss and partial overlap in dominant clones between biological replicates [1]. To identify the source of these observations, we build a computational model that simulates the iterated growth and passage experiments. By varying the 'division rules' in the model, we can quantitatively predict the evolution of the clone distribution for the aforementioned hypotheses. In this manner, we show that clonal dominance does not appear in simulations where all cells divide at a uniform rate, even when the population is subdivided in cancer stem cells and differentiated cells. However, when the division rates vary between clones and are inherited from parent cells, dominant clones appear. These simulations also closely match the in vitro evolution of clone loss and clonal overlap between biological replicates. Altogether, our findings suggest that tumor cells exhibit a heritable variability in the division rates of individual cells. References [1] Porter, S. et al. (2014). Lentiviral and targeted cellular barcoding reveals ongoing clonal dynamics of cell lines in vitro and in vivo. Genome Biology, 15(5), R75. Citation Format: Margriet M. Palm, Marjet Elemans, Joost B. Beltman. Tumor cell division rate heterogeneity explains in vitro clonal dominance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4535. doi:10.1158/1538-7445.AM2017-4535