Quantifying metastatic inefficiency: rare genotypes versus rare dynamics

We introduce and solve a 'null model' of stochastic metastatic colonization. The model is described by a single parameter ?: the ratio of the rate of cell division to the rate of cell death for a disseminated tumour cell in a given secondary tissue environment. We are primarily interested in the case in which colonizing cells are poorly adapted for proliferation in the local tissue environment, so that cell death is more likely than cell division, i.e. ? 1, we find that the probability of establishment is exponentially rare, as expected, and yet the mean time for such rare events is of the form ~log (N)/(1 - ?) while the standard deviation of colonization times is ~1/(1 - ?). Thus, counter to naive expectation, for ? 1), i.e. the statistics show a duality mapping (1 - ?) --> (? - 1). We conclude our analysis with a study of heterogeneity in the fitness of colonising cells, and describe a phase diagram delineating parameter regions in which metastatic colonization is dominated either by low or high fitness cells, showing that both are plausible given our current knowledge of physiological conditions in human cancer.