The evolution of metastasis represents a lethal and incurable stage of cancer progression. Yet, the evolutionary kinetics that drive the emergence of metastasis remain broadly unresolved. Utilizing a Bayesian phylogenetic comparative approach, we have quantified the single cell evolutionary kinetics of metastatic lung in mice engineered with a Crispr-Cas9 lineage recorder. First, for each metastatic lineage, we reconstructed a posterior distribution of single cell phylogenetic trees using a Reversible-jump Markov Chain Monte Carlo (RJMCMC) framework. The RJMCMC framework is important because it allows us to account for the spatial and temporal heterogeneity in mutation rates that arise because of the Crispr-Cas9 system whilst also capturing the uncertainty in tree topology that is inherent in phylogenetic reconstruction. Once finished, we calculated the amount of evolutionary change that had occurred for each cell as the sum of the individual branch lengths from root to tip in the phylogenetic tree, known as the path length, as well as the number of diversification events, the nodes. Next, we tested for evidence of gradual and punctuated evolution in each tree by fitting a phylogenetic least squares regression between the number of nodes and total path length. A gradual model of tumor evolution posits that mutations occur homogenously across the population through time and thus the number of diversification events, nodes, is expected to be independent of the amount of evolutionary change that has occurred. In contrast, a punctuated model of tumor evolution postulates that diversification is associated with short intense bursts of evolutionary change and thus the number of diversification events is expected to be positively correlated with the amount of evolutionary change that has occurred. We found that signatures of punctuated evolution were present in all metastatic lineages. However, within the same metastatic lineage, the punctuated effect size was significantly larger in cells that have metastasized to a distant organ compared to cells that remain within the primary tumor. Taken together, these findings suggest that punctuated effects are pervasive, and that strong punctuated effects may be a hallmark of successful metastatic dissemination. Future work will look to identify the evolutionary timing of the punctuated effects to determine whether they occur within the primary tumor prior to dissemination or whether they occur once the cells have arrived at a distant site.
© 2026 - The Mathematical Oncology Blog
© 2026 - The Mathematical Oncology Blog