AbstractSummaryMetastases form by dispersal of cancer cells to secondary tissues. They cause a vast majority of cancer morbidity and mortality. Metastatic clones are not medically detected or visible until later stages of cancer development. Thus, clone phylogenies within patients provide a means of tracing the otherwise inaccessible dynamic history of migrations of cancer cells. Here we present a new Bayesian approach,PathFinder, for reconstructing the routes of cancer cell migrations.PathFinderuses the clone phylogeny and the numbers of mutational differences among clones, along with the information on the presence and absence of observed clones in different primary and metastatic tumors. In the analysis of simulated datasets,PathFinderperformed well in reconstructing migrations from the primary tumor to new metastases as well as between metastases. However, it was much more challenging to trace migrations from metastases back to primary tumors. We found that a vast majority of errors can be corrected by sampling more clones per tumor and by increasing the number of genetic variants assayed. We also identified situations in which phylogenetic approaches alone are not sufficient to reconstruct migration routes.ConclusionsWe anticipate that the use ofPathFinderwill enable a more reliable inference of migration histories, along with their posterior probabilities, which is required to assess the relative preponderance of seeding of new metastasis by clones from primary tumors and/or existing metastases.AvailabilityPathFinder is available on the web athttps://github.com/SayakaMiura/PathFinder.Contacts.kumar@temple.edu