Elements and evolutionary determinants of genomic divergence between paired primary and metastatic tumors
Fig 3
Single-cell-based spatial simulation of paired metastatic and primary tumors validates the phylogenetic definition of Bmd and emphasizes that Bm can appear sensitive or insensitive to seeding time based on the kinetics of primarty tumor growth.
(A)Bmd, the sub branch length (measured in cell generations) from the metastatic seeding cell to its most recent detectable ancestor (MRDAα) captures the majority of the variance of Bm measured from the virtual tumors (green density curves). By contrast, the tumor size at metastatic dissemination, as a surrogate of dissemination time (gray density curves) does not faithfully explain the measured Bm. (B) Two virtual tumors with distinct kinetics exemplify the conditional dependence of Bm on metastatic dissemination time. Upper panel: the genealogy trajectories (gray lines) of metastatic seeding cells (green dots) along the expansion of the primary tumor in a three dimensional lattice. The Euclidean distance from a cell to the center of the lattice is shown against the tumor size fraction when the corresponding cell disseminates. A cell’s distance to the center is strongly correlated with its mutation burden (S3 Fig), reflecting the spatial constraints imposed in our model. The tumor size fraction is plotted at its cube root scale to reflect the clock of actual time. Ancestor cells that are detectable at a frequency greater than 0.01 are marked as blue dots; Middle panel: Bm is plotted against the tumor size fraction when the seeding cell (green dots) disseminates, the running mean (black dots) and standard deviation (gray bars) is also shown; Lower panel: Bm is shown against the Bmd, the sub-branch length from the seeding cell to its MRDAα. The slope of the linear regression is consistent with the passenger variant rate (0.15) used in the model, CI: 95% confidence interval.