Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution

Deep-genome and single-cell sequencing analyses of patient-derived breast cancer xenografts reveal extensive, dynamic and reproducible changes in intra-tumoral mutational clonal composition on engraftment and serial propagation. Clonal evolution in xenograft tumours Xenograft transplantation of primary human cancer cells into mice provides valuable models in which to study mechanisms underlying tumorigenesis, drug response and resistance. This study demonstrates that clonal evolution resembling that seen in human tumours also occurs on engraftment and during subsequent passaging of breast tumours in immunodeficient mice. In addition, similar clonal expansion patterns emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. These findings suggest that patient-derived xenografts may be useful for studying patient-specific tumour characteristics such as the response to drugs tailored to specific genomic alterations. Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution 1 , 2 , underpinning important emergent features such as drug resistance and metastasis 3 , 4 , 5 , 6 , 7 . Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours 8 , 9 , 10 . However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (