  The dynamics of tumor cell populations is hotly debated: do populations
derive hierarchically from a subpopulation of cancer stem cells (CSCs), or are
stochastic transitions that mutate differentiated cancer cells to CSCs
important? Here we argue that regulation must also be important. We sort human
melanoma cells using three distinct cancer stem cell (CSC) markers - CXCR6,
CD271 and ABCG2 - and observe that the fraction of non-CSC-marked cells first
overshoots to a higher level and then returns to the level of unsorted cells.
This clearly indicates that the CSC population is homeostatically regulated.
Combining experimental measurements with theoretical modeling and numerical
simulations, we show that the population dynamics of cancer cells is associated
with a complex miRNA network regulating the Wnt and PI3K pathways. Hence
phenotypic switching is not stochastic, but is tightly regulated by the balance
between positive and negative cells in the population. Reducing the fraction of
CSCs below a threshold triggers massive phenotypic switching, suggesting that a
therapeutic strategy based on CSC eradication is unlikely to succeed.
