Initiation of Micro-Metastases from Low-Fitness Cancer Cells: Rare, Explosive, and Deterministic

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The final stage of the metastatic cascade, colonization of secondary tissue sites, is very hard to address experimentally and is thus poorly understood. Given the long time-scale of most metastatic disease, it is commonly presumed that colonization arises from rare genetically pre-adapted founding cells. We construct a null model to estimate the relative probability of colonization from common non-pre-adapted cancer cells. We find that the dynamics of rare colonization events in this cell population is explosive and essentially deterministic, and thus indistinguishable from colonization dynamics from pre-adapted cells. And we find, in comparing relative likelihoods of pre-adapted and non-pre-adapted cells, that the latter can dominate if early metastatic tumors self-stabilize at a scale of 20-40 cells. We term this speculative tumor stage as a ‘proto-metastasis’, and comment on how these new insights may lead to new therapeutic interventions of metastatic disease. This is work in progress done in collaboration with Timothy Newman at The University of Dundee.