PT - JOURNAL ARTICLE AU - Johannes G. Reiter AU - Shriya Nagpal AU - Kamila Naxerova TI - Lymphatic metastases have more diverse roots than distant metastases AID - 10.1101/828913 DP - 2019 Jan 01 TA - bioRxiv PG - 828913 4099 - http://biorxiv.org/content/early/2019/11/02/828913.short 4100 - http://biorxiv.org/content/early/2019/11/02/828913.full AB - Both lymphatic and distant metastases arise through cancer cell migration and colonization of ectopic sites. Nonetheless, the two metastasis types are associated with significantly different clinical outcomes, suggesting that distinct biological mechanisms may drive their formation. Here we show fundamental differences in the seeding patterns of lymphatic and distant metastases. Analyzing the reconstructed phylogenies of human colorectal cancers, we find that distant metastases typically are monophyletic, originating from one common ancestor. Lymphatic metastases, in contrast, are almost exclusively polyphyletic and can be seeded from many primary tumor regions. We develop a rigorous mathematical framework for quantifying the phylogenetic diversity of metastases while accounting for differential lesion sampling among patients. Our results indicate that a smaller fraction of primary tumor cells gives rise to distant metastases than lymphatic metastases. Thus, the two metastasis types exhibit profoundly distinct phylogenetic traits, indicating that different evolutionary mechanisms may drive their formation and influence their clinical behavior.