Overshoot during phenotypic switching of cancer cell populations

TL;DR

This paper demonstrates that cancer stem cell populations in melanoma are homeostatically regulated through complex miRNA networks, challenging stochastic models and impacting therapeutic strategies targeting CSC eradication.

Contribution

It provides experimental evidence of regulated phenotypic switching in cancer cells and integrates theoretical modeling to explain the underlying mechanisms.

Findings

CSC fractions overshoot and then stabilize, indicating regulation

miRNA networks control Wnt and PI3K pathways in phenotypic switching

Reducing CSCs below a threshold triggers massive switching

Abstract

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.