Intratumor Heterogeneity and Circulating Tumor Cell Clusters

Abstract

Genetic diversity plays a central role in tumor progression, metastasis, and resistance to treatment. Experiments are shedding light on this diversity at ever finer scales, but interpretation is challenging. Using recent progress in numerical models, we simulate macroscopic tumors to investigate the interplay between growth dynamics, microscopic composition, and circulating tumor cell cluster diversity. We find that modest differences in growth parameters can profoundly change microscopic diversity. Simple outwards expansion leads to spatially segregated clones and low diversity, as expected. However, a modest cell turnover can result in an increased number of divisions and mixing among clones resulting in increased microscopic diversity in the tumor core. Using simulations to estimate power to detect such spatial trends, we find that multiregion sequencing data from contemporary studies is marginally powered to detect the predicted effects. Slightly larger samples, improved detection of rare variants, or sequencing of smaller biopsies or circulating tumor cell clusters would allow one to distinguish between leading models of tumor evolution. The genetic composition of circulating tumor cell clusters, which can be obtained from non-invasive blood draws, is therefore informative about tumor evolution and its metastatic potential.\n\nHighlightsO_LINumerical and theoretical models show interaction of front expansion, mutation, and clonal mixing in shaping tumor heterogeneity.\nC_LIO_LICell turnover increases intratumor heterogeneity.\nC_LIO_LISimulated circulating tumor cell clusters and microbiopsies exhibit substantial diversity with strong spatial trends.\nC_LIO_LISimulations suggest attainable sampling schemes able to distinguish between prevalent tumor growth models.\nC_LI