Quantifying metastasis heterogeneity in colorectal cancer

Metastasis is a process that in humans takes place completely unobserved, over long time periods, and we know very little about it. Animal models are valuable tools for studying metastasis mechanistically, but only if we have an accurate picture of the metastatic process in humans, so that we can select the most appropriate models and ask the right questions. One our lab’s main interests are host organ-specific metastasis patterns. It is currently unknown whether metastases in different organs form through distinct evolutionary mechanisms, although different metastasis types display divergent clinical behavior. We have evidence to suggest that the characteristics of colorectal cancer metastases - in particular their genetic diversity and their phylogenetic relationships to the primary tumor – differ by host organ. We are taking advantage of a unique collection of multi-region sampled metastatic colorectal cancer cases that we have been building over years, encompassing more than 1000 distinct tumor samples from more than 100 patients. We have reconstructed phylogenetic trees that visualize the evolutionary history of these cancers and find recurrent, quantifiable differences in the position of different metastasis types on the phylogenetic trees. For example, liver metastases are homogeneous and diverge late in tumor evolution, indicating late metastatic seeding by single cells or small groups of cells. Their inter-lesion uniformity suggests selection for a liver-competent growth phenotype. Locoregional lymph node metastases, in contrast, are highly diverse and associate closely with the primary tumor, indicating continuous seeding and comparatively mild selection pressure. The unique phylogenetic patterns associated with different metastasis type encode important information about formation mechanisms and have implications for surgical and medical treatment.