Abstract 3759: Xenograft rebound kinetics are consistent with the founder effect

Abstract

Abstract Introduction Tumors are often composed of a heterogeneous cell population growing over time subject to the forces of evolutionary dynamics. These principles offer insights not only for bulk tumor growth, but also for small cell populations such as in metastases or de-bulked tumors following treatment. In this work, we investigate whether the evolutionary effects of small population sizes are evident in in vivo pre-clinically through a meta-analysis of xenograft rebound growth kinetics following treatment. Methods We first used a HCT116 cell fitness distribution we have previously measured in soft agar to demonstrate the expected population fitness trajectory as a function of starting population size. We sampled subclone fitnesses from this distribution to initialize either large or small theoretical tumors, and simulated tumor growth as a Moran process to find the probability distribution of expected outcomes in final tumor population fitness. Since initial tumor volumes in xenografts experiments have a narrow range of volume (equivalently, population size), we next identified tumor volume measurements following suspension of treatment with anticancer agents from in-house historical xenograft growth datasets. Each of 1359 tumor volume trajectories after treatment was fit using non-linear regression to determine the exponential growth rate (population fitness), and compared to both the volume at treatment end as well as the average control group growth rate from the corresponding experiment. Results The simulated tumors demonstrate the “founder effect” in heterogeneous populations: large populations become dominated by the fastest growing, most fit subclones while small populations are sensitive to initial clonal sampling as well as random births and deaths. Rebound growth in xenografts post-treatment displayed large variability compared to the growth of the corresponding experimental control group. Post-treatment and untreated growth rates are poorly correlated (R2 = 0.1) consistent with a significant change in the tumor cell population following a period of selective pressure. Two additional observations are coherent with a founder effect following a bottleneck event (i.e., treatment). The relationship between post-treatment starting volume and growth rate has a positive slope (p = 0.01, F-test) while growth rate variance decreases with starting volume (p < 0.01 F-test). Both results concur with the Moran simulations showing smaller populations have more stochastic outcomes while larger populations deterministically drift to greater fitness. Conclusions We find that xenograft growth kinetics following cessation of treatment with anticancer agents are consistent with a selection process and the founder effect. Application of evolutionary theory to small cell populations in preclinical models may yield new strategies to combat metastases and resistance emergence. Citation Format: Andrew Chen, Christopher J. Zopf, Jing-Tao Wu, Wen Chyi Shyu, Arijit Chakravarty. Xenograft rebound kinetics are consistent with the founder effect. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3759. doi:10.1158/1538-7445.AM2015-3759